Anshu Bhardwaj

Long term fellow
Who I am

I did Masters in Biotech followed by Ph.D. in Life Sciences (Comp bio) at Centre for Cellular & Molecular Biology, Hyderabad, India, in 2008. I then served as one of the founding PIs for Open Source Drug Discovery Project where I conceived & developed protocols for crowdsourcing drug discovery. I enjoy working with anyone who has interest in addressing public health challenges. I have a large network on students (who I call SciTechtives) with whom I co-develop tools for data analysis.
What I do at CRI

My primary research interest is to develop tools to address antimicrobial resistance (AMR). In CRI, I shall be working on genomic signatures to identify priority pathogens. In addition, I am also developing a gaming app for creating awareness on AMR. Both these objectives align with the Global Action Plan on AMR. For the project, I will utilize my experience in crowdsourcing, functional & comparative genomics & computational drug discovery and the wonderful ecosystem of CRI.
Research Projects

Genomic signatures to identify non-tubercular Mycobacterial species
People involved: Anshu Bhardwaj Keywords: genomics, biomarker, pathogen, nontuberculous mycobacteria, AI chatbot, gaming Project Description Antimicrobial resistance (AMR), the phenomenon of clinically relevant pathogens developing multi-drug resistance (particularly to antibiotics), has emerged as a grave threat to public health that could plunge the world into a ‘post-antibiotic era’. Neglecting AMR would result in global annual loss of 10 million lives and trillions of dollars by 2050 (2015 O’Neil). The Global Action Plan for AMR has identified five objectives to address this scourge. The first two objectives - “ (a) Improve awareness and understanding of antimicrobial resistance through effective communication, education and training and (b) Strengthen the knowledge and evidence base through surveillance and research” are the basis of the current proposal which aims to address these using genomics and artificial intelligence tools. At the core of the project is the pressing need to identify infections from Nontuberculous mycobacteria (NTM) or Mycobacterial Other Than TB (MOTT). NTMs include more than 160 ubiquitous Mycobacterium species that do not cause tuberculosis or leprosy. NTMs are present in the environment (water or soil) and can infect humans or animals leading to a range of pathological conditions like pulmonary, skin, bone, joint, and disseminated diseases. NTM species are gaining visibility due an increasing number of strains responsible for treatment-resistant diseases. NTMs are taxonomical diverse and increasing number of new species offer challenges in identification of NTMs in clinical settings. NTM species like Mycobacterium abscessus are now recognized as a major threat and FDA identified NTMs as their focus disease area in 2016-17. Despite their increasing role in human diseases (in India prevalence rate increased from 0.7% to 34%) limited data is available to delineate and identify species of NTMs in the clinical settings. It is crucial to know the NTM species for prescribing treatment options as the disease presentation and clinical investigation parameters are very similar to Tuberculosis. Moreover, there are species-specific differences from context of resistance to different antibiotics. The current proposal entitled ‘G-MOTT’ aims to develop a comparative genomics pipeline to identify genomic signatures that may help in delineating different NTM species. The second part of the proposal aims to build a conversational artificial intelligence (AI) chatbot wrapped as a gaming application. The idea behind building this tool is to engage the mobile users into playing a game to understand the concept and challenges of AMR. This is first of its kind unique effort to utilize the power of AI to strengthen the human-machine interface aligning with the goals of the Global Action Plan on creating awareness, education and training on AMR.

I served as an Associate Scientific Advisor to Science Translational Medicine in 2014 and am on the Editorial Board of Frontiers in Systems Biology and Journal of Genetics. In addition, I was selected as one of the four Young Innovators in India by the United National Development Program (UNDP). Also selected for the International Visitor Leadership Program by the US State Department. Recently, I received the Newton-Bhabha Fund from the British Council and the Royal Society of Chemistry, UK, and SERB Early Career Research Award by SERB, India. Till date, I have delivered over 150 talks at national and international platforms. I describe myself as a people's person, I like interacting with individuals from different research and subject interests and believe in team building.


I am looking for a vibrant post-doc.. Details here - https://research.cri-paris.org/jobs/postdoc-bhardwaj/

Publications

Genetic landscape of the people of India: a canvas for disease gene exploration
Samir Brahmachari and Partha Majumder and Mitali Mukerji and Saman Habib and Debasis Dash and Kunal Ray and Samira Bahl and Jyotsna Batra
Journal of Genetics
87
3-20
Open source drug discovery–a new paradigm of collaborative research in tuberculosis drug development
Anshu Bhardwaj and Vinod Scaria and Gajendra Pal Singh Raghava and Andrew Michael Lynn and Nagasuma Chandra and Sulagna Banerjee and Muthukurussi V Raghunandanan and Vikas Pandey and Bhupesh Taneja and Jyoti Yadav and Debasis Dash and Jaijit Bhattacharya and Amit Misra and Anil Kumar and Srinivasan Ramachandran and Zakir Thomas and Samir K Brahmachari and Open Source Drug Discovery Consortium
It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug …
Tuberculosis
91
479-486
10.1016/j.tube.2011.06.004
Crowd sourcing a new paradigm for interactome driven drug target identification in Mycobacterium tuberculosis
Rohit Vashisht and Anupam Kumar Mondal and Akanksha Jain and Anup Shah and Priti Vishnoi and Priyanka Priyadarshini and Kausik Bhattacharyya and Harsha Rohira and Ashwini G Bhat and Anurag Passi and Keya Mukherjee and Kumari Sonal Choudhary and Vikas Kumar and Anshula Arora and Prabhakaran Munusamy and Ahalyaa Subramanian and Aparna Venkatachalam and S Gayathri and Sweety Raj and Vijaya Chitra and Kaveri Verma and Salman Zaheer and J Balaganesh and Malarvizhi Gurusamy and Mohammed Razeeth and Ilamathi Raja and Madhumohan Thandapani and Vishal Mevada and Raviraj Soni and Shruti Rana and Girish Muthagadhalli Ramanna and Swetha Raghavan and Sunil N Subramanya and Trupti Kholia and Rajesh Patel and Varsha Bhavnani and Lakavath Chiranjeevi and Soumi Sengupta and Pankaj Kumar Singh and Naresh Atray and Swati Gandhi and Tiruvayipati Suma Avasthi and Shefin Nisthar and Meenakshi Anurag and Pratibha Sharma and Yasha Hasija and Debasis Dash and Arun Sharma and Vinod Scaria and Zakir Thomas and Nagasuma Chandra and Samir K Brahmachari and Anshu Bhardwaj and OSDD Consortium
A decade since the availability of Mycobacterium tuberculosis (Mtb) genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative ‘Connect to Decode’ (C2D) to generate the first and largest manually curated interactome of Mtb termed ‘interactome pathway’ (IPW), encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach.
PloS one
7
e39808
10.1371/journal.pone.0039808
Structural annotation of Mycobacterium tuberculosis proteome
Praveen Anand and Sandhya Sankaran and Sumanta Mukherjee and Kalidas Yeturu and Roman Laskowski and Anshu Bhardwaj and Raghu Bhagavat and Samir K Brahmachari and Nagasuma Chandra and OSDD Consortium
Of the ∼4000 ORFs identified through the genome sequence of Mycobacterium tuberculosis (TB) H37Rv, experimentally determined structures are available for 312. Since knowledge of protein structures is essential to obtain a high-resolution understanding of the underlying biology, we seek to obtain a structural annotation for the genome, using computational methods. Structural models were obtained and validated for ∼2877 ORFs, covering ∼70% of the genome. Functional annotation of each protein was based on fold-based functional assignments and a novel binding site based ligand association. New algorithms for binding site detection and genome scale binding site comparison at the structural level, recently reported from the laboratory, were utilized. Besides these, the annotation covers detection of various sequence and sub-structural motifs and quaternary structure predictions based on the corresponding templates. The study provides an opportunity to obtain a global perspective of the fold distribution in the genome. The annotation indicates that cellular metabolism can be achieved with only 219 folds. New insights about the folds that predominate in the genome, as well as the fold-combinations that make up multi-domain proteins are also obtained. 1728 binding pockets have been associated with ligands through binding site identification and sub-structure similarity analyses. The resource (http://proline.physics.iisc.ernet.in/Tbstructuralannotation), being one of the first to be based on structure-derived functional annotations at a genome scale, is expected to be useful for better understanding of TB and for application in drug …
PLoS One
6
e27044
10.1371/journal.pone.0027044
TBrowse: an integrative genomics map of Mycobacterium tuberculosis
Anshu Bhardwaj and Deeksha Bhartiya and Nitin Kumar and Vinod Scaria
Tuberculosis is one of the major infectious diseases causing morbidity and mortality in the developing world. Genome-wide experiments on Mycobacterium tuberculosis particularly H37Rv and many other strains has revealed a wealth of information on the pathogen. This has been complemented by computational methods for the analysis of genomic sequence. This genome-level information is scattered in individual databases and supplementary material of publications and is not easily amenable to integrative analysis and visualization. TBrowse is an attempt to create a starting resource for integrative analysis of the M. tuberculosis genome. This comprehensive database contains more than half a million data-points of genomic data systematically culled from online resources and publications and is organized into hundred tracks. The resource is built based on the Generic Model Organism Database Genome …
Tuberculosis
89
386-387
10.1016/j.tube.2009.07.005
BioPhytMol: a drug discovery community resource on anti-mycobacterial phytomolecules and plant extracts
Arun Sharma and Prasun Dutta and Maneesh Sharma and Neeraj Kumar Rajput and Bhavna Dodiya and John J Georrge and Trupti Kholia and Anshu Bhardwaj and OSDD Consortium
Tuberculosis (TB) is the second leading cause of death from a single infectious organism, demanding attention towards discovery of novel anti-tubercular compounds. Natural products or their derivatives have provided more than 50% of all existing drugs, offering a chemically diverse space for discovery of novel drugs. BioPhytMol has been designed to systematically curate and analyze the anti-mycobacterial natural product chemical space. BioPhytMol is developed as a drug-discovery community resource with anti-mycobacterial phytomolecules and plant extracts. Currently, it holds 2582 entries including 188 plant families (692 genera and 808 species) from global flora, manually curated from literature. In total, there are 633 phytomolecules (with structures) curated against 25 target mycobacteria. Multiple analysis approaches have been used to prioritize the library for drug-like compounds, for both whole cell screening and target-based approaches. In order to represent the multidimensional data on chemical diversity, physiochemical properties and biological activity data of the compound library, novel approaches such as the use of circular graphs have been employed. BioPhytMol has been designed to systematically represent and search for anti-mycobacterial phytochemical information. Extensive compound analyses can also be performed through web-application for prioritizing drug-like compounds. The resource is freely available online at http://ab-openlab.csir.res.in/biophytmol/ . Graphical Abstract BioPhytMol: a drug discovery community …
Journal of Cheminformatics
6
1-10
10.1186/s13321-014-0046-2
MtSNPscore: a combined evidence approach for assessing cumulative impact of mitochondrial variations in disease
Anshu Bhardwaj and Mitali Mukerji and Shipra Sharma and Jinny Paul and Chaitanya S Gokhale and Achal K Srivastava and Shrish Tiwari
Human mitochondrial DNA (mtDNA) variations have been implicated in a broad spectrum of diseases. With over 3000 mtDNA variations reported across databases, establishing pathogenicity of variations in mtDNA is a major challenge. We have designed and developed a comprehensive weighted scoring system (MtSNPscore) for identification of mtDNA variations that can impact pathogenicity and would likely be associated with disease. The criteria for pathogenicity include information available in the literature, predictions made by various in silico tools and frequency of variation in normal and patient datasets. The scoring scheme also assigns scores to patients and normal individuals to estimate the cumulative impact of variations. The method has been implemented in an automated pipeline and has been tested on Indian ataxia dataset (92 individuals), sequenced in this study, and other publicly available mtSNP dataset comprising of 576 mitochondrial genomes of Japanese individuals from six different groups, namely, patients with Parkinson's disease, patients with Alzheimer's disease, young obese males, young non-obese males, and type-2 diabetes patients with or without severe vascular involvement. MtSNPscore, for analysis can extract information from variation data or from mitochondrial DNA sequences. It has a web-interface http://bioinformatics.ccmb.res.in/cgi-bin/snpscore/Mtsnpscore.pl that provides flexibility to update/modify the parameters for estimating pathogenicity. Analysis of ataxia and mtSNP data suggests that rare variants comprise the largest part of disease associated variations …
BMC bioinformatics
10
S7
10.1186/1471-2105-10-s8-s7
Systems level mapping of metabolic complexity in Mycobacterium tuberculosis to identify high-value drug targets
Rohit Vashisht and Ashwini G Bhat and Shreeram Kushwaha and Anshu Bhardwaj and Samir K Brahmachari and OSDD Consortium
The effectiveness of current therapeutic regimens for Mycobacterium tuberculosis (Mtb) is diminished by the need for prolonged therapy and the rise of drug resistant/tolerant strains. This global health threat, despite decades of basic research and a wealth of legacy knowledge, is due to a lack of systems level understanding that can innovate the process of fast acting and high efficacy drug discovery. The enhanced functional annotations of the Mtb genome, which were previously obtained through a crowd sourcing approach was used to reconstruct the metabolic network of Mtb in a bottom up manner. We represent this information by developing a novel Systems Biology Spindle Map of Metabolism (SBSM) and comprehend its static and dynamic structure using various computational approaches based on simulation and design. The reconstructed metabolism of Mtb encompasses 961 metabolites, involved in 1152 reactions catalyzed by 890 protein coding genes, organized into 50 pathways. By accounting for static and dynamic analysis of SBSM in Mtb we identified various critical proteins required for the growth and survival of bacteria. Further, we assessed the potential of these proteins as putative drug targets that are fast acting and less toxic. Further, we formulate a novel concept of metabolic persister genes (MPGs) and compared our predictions with published in vitro and in vivo experimental evidence. Through such analyses, we report for the first time that de novo biosynthesis of NAD may give rise to bacterial persistence in Mtb under conditions of metabolic stress induced by conventional anti-tuberculosis therapy. We propose such MPG's …
Journal of translational medicine
12
263
10.1186/s12967-014-0263-5
Open Source Software and Web Services for Designing Therapeutic Molecules
Deepak Singla and Sandeep Kumar Dhanda and Jagat Singh Chauhan and Anshu Bhardwaj and Samir K Brahmachari and Gajendra PS Raghava
Despite the tremendous progress in the field of drug designing, discovering a new drug molecule is still a challenging task. Drug discovery and development is a costly, time consuming and complex process that requires millions of dollar and 10-15 years to bring new drug molecules in the market. This huge investment and long-term process are attributed to high failure rate, complexity of the problem and strict regulatory rules, in addition to other factors. Given the availability of ‘big’ data with ever improving computing power, it is now possible to model systems which is expected to provide time and cost effectiveness to drug discovery process. Computer Aided Drug Designing (CADD) has emerged as a fast alternative method to bring down the cost involved in discovering a new drug. In past, numerous computer programs have been developed across the globe to assist the researchers working in the field of drug …
Current topics in medicinal chemistry
13
1172-1191
10.2174/1568026611313100005
MitoLSDB: A Comprehensive Resource to Study Genotype to Phenotype Correlations in Human Mitochondrial DNA Variations
K Shamnamole and Saakshi Jalali and Vinod Scaria and Anshu Bhardwaj
Human mitochondrial DNA (mtDNA) encodes a set of 37 genes which are essential structural and functional components of the electron transport chain. Variations in these genes have been implicated in a broad spectrum of diseases and are extensively reported in literature and various databases. In this study, we describe MitoLSDB, an integrated platform to catalogue disease association studies on mtDNA (http://mitolsdb.igib.res.in). The main goal of MitoLSDB is to provide a central platform for direct submissions of novel variants that can be curated by the Mitochondrial Research Community. MitoLSDB provides access to standardized and annotated data from literature and databases encompassing information from 5231 individuals, 675 populations and 27 phenotypes. This platform is developed using the Leiden Open (source) Variation Database (LOVD) software. MitoLSDB houses information on all 37 genes in each population amounting to 132397 variants, 5147 unique variants. For each variant its genomic location as per the Revised Cambridge Reference Sequence, codon and amino acid change for variations in protein-coding regions, frequency, disease/phenotype, population, reference and remarks are also listed. MitoLSDB curators have also reported errors documented in literature which includes 94 phantom mutations, 10 NUMTs, six documentation errors and one artefactual recombination. MitoLSDB is the largest repository of mtDNA variants systematically standardized and presented using the LOVD platform. We believe that this is a good starting resource to curate mtDNA variants and will facilitate direct submissions …
PloS one
8
e60066
10.1371/journal.pone.0060066
dPABBs: a novel in silico approach for predicting and designing anti-biofilm peptides
Arun Sharma and Pooja Gupta and Rakesh Kumar and Anshu Bhardwaj
Increasingly, biofilms are being recognised for their causative role in persistent infections (like cystic fibrosis, otitis media, diabetic foot ulcers) and nosocomial diseases (biofilm-infected vascular catheters, implants and prosthetics). Given the clinical relevance of biofilms and their recalcitrance to conventional antibiotics, it is imperative that alternative therapeutics are proactively sought. We have developed dPABBs, a web server that facilitates the prediction and design of anti-biofilm peptides. The six SVM and Weka models implemented on dPABBs were observed to identify anti-biofilm peptides on the basis of their whole amino acid composition, selected residue features and the positional preference of the residues (maximum accuracy, sensitivity, specificity and MCC of 95.24%, 92.50%, 97.73% and 0.91, respectively, on the training datasets). On the N-terminus, it was seen that either of the cationic polar residues …
Scientific reports
6
21839
10.1038/srep21839
Analysis of the DosR regulon genes to select cytotoxic T lymphocyte epitope specific vaccine candidates using a reverse vaccinology approach
Kirti Pandey and Monika Sharma and Iti Saarav and Swati Singh and Prasun Dutta and Anshu Bhardwaj and Sadhna Sharma
Objective/backgroundThere is an urgent need for a more effective vaccine against Mycobacterium tuberculosis (Mtb). Although CD4+ T cells play a central role in host immunity to Mtb, recent evidence suggests a critical role of CD8+ T cells in combating Mtb. In the present study, we have predicted HLA antigen class I binding peptides of DosR operon using an in-silico approach. This method is useful as an initial computational filtration of probable epitopes based on their binding ability and antigenicity.MethodsCD8+ epitopes were predicted by software NetMHC 3.4 and BIMAS. Self-peptides were found and excluded by indigenously developed Perl script. Antigenicity of promiscuous peptides was predicted using a VaxiJen server. The top VaxiJen scoring antigenic peptides were docked to globally relevant HLA allele using CABS dock and Hex program.ResultsA total of 1436 overlapping nonamer peptides were …
International journal of mycobacteriology
5
34-43
10.1016/j.ijmyco.2015.10.005
Social networks to biological networks: systems biology of Mycobacterium tuberculosis
Rohit Vashisht and Anshu Bhardwaj and Samir K Brahmachari and Osdd Consortium
Contextualizing relevant information to construct a network that represents a given biological process presents a fundamental challenge in the network science of biology. The quality of network for the organism of interest is critically dependent on the extent of functional annotation of its genome. Mostly the automated annotation pipelines do not account for unstructured information present in volumes of literature and hence large fraction of genome remains poorly annotated. However, if used, this information could substantially enhance the functional annotation of a genome, aiding the development of a more comprehensive network. Mining unstructured information buried in volumes of literature often requires manual intervention to a great extent and thus becomes a bottleneck for most of the automated pipelines. In this review, we discuss the potential of scientific social networking as a solution for systematic …
Molecular BioSystems
9
1584-1593
10.1039/c3mb25546h
FishMap Zv8 Update—A Genomic Regulatory Map of Zebrafish
Deeksha Bhartiya and Jayant Maini and Meenakshi Sharma and Prateek Joshi and Saurabh V Laddha and Saakshi Jalali and Ashok Patowary and Ramya Purkanti and Mukesh Lalwani and Angom Ramcharan Singh and Rajendra Chauhan and Naresh Singh and Anshu Bhardwaj and Vinod Scaria and Sridhar Sivasubbu
The advancements in genomics technologies and the amenability to large-scale computational analysis have contributed immensely to the understanding of the zebrafish genome, its organization, and its functional correlates. Translating genomics information into biological meaning would require integration and amenability of data and tools. FishMap is a community resource for genomic datasets on zebrafish created with a vision to provide relevant and readily available information to zebrafish researchers. The present update of FishMap has kept up with the availability of the latest zebrafish genome assembly (Zv8). In this update, particular emphasis has been given to noncoding RNAs and noncoding RNA-mediated regulation in addition to genomic regulatory motifs, which are emerging areas of vertebrate biology. FishMap Zv8 update also features a sequence mapping and analysis server. Consistent with its …
Zebrafish
7
179-180
10.1089/zeb.2009.0624
Predicting promiscuous antigenic T cell epitopes of Mycobacterium tuberculosis mymA operon proteins binding to MHC Class I and Class II molecules
Iti Saraav and Kirti Pandey and Monika Sharma and Swati Singh and Prasun Dutta and Anshu Bhardwaj and Sadhna Sharma
Limited efficacy of Bacillus Calmette–Guérin vaccine has raised the need to explore other immunogenic candidates to develop an effective vaccine against Mycobacterium tuberculosis (Mtb). Both CD4 + and CD8 + T cells play a critical role in host immunity to Mtb. Infection of macrophages with Mtb results in upregulation of mymA operon genes thereby suggesting their importance as immune targets. In the present study, after exclusion of self-peptides mymA operon proteins of Mtb were analyzed in silico for the presence of Human Leukocyte Antigen (HLA) Class I and Class II binding peptides using Bioinformatics and molecular analysis section, NetMHC 3.4, ProPred and Immune epitope database software. Out of 56 promiscuous epitopes obtained, 41 epitopes were predicted to be antigenic for MHC Class I. In MHC Class II, out of 336 promiscuous epitopes obtained, 142 epitopes were predicted to be antigenic …
Infection, Genetics and Evolution
44
182-189
10.1016/j.meegid.2016.07.004
Harnessing the Crowd for Neurology Research
Anshu Bhardwaj
The first problem attacked by crowdsourcing was probably the 1714 Longitude Prize—for a marine clock that would enable accurate calculation of longitude at sea—but subsequent efforts such as Wikipedia in 2001 and Open Source Drug Discovery in 2007 have proven the power of this approach. Now, Brown et al. harness Internet-enabled mobile phones to push further the boundaries of such community experiments. These authors have designed smartphone games to engage large numbers of people in a cognitive science study. Their results show that a big sample size can outweigh the added error inherent in collection of data outside the lab, affirming the potential of crowdsourcing as a powerful scientific tool.Brown et al. designed four short games entitled “The Great Brain Experiment.” One of these tests the players’ ability to inhibit their own actions. In this game, participants tap fruit falling from a tree when it …
Science Translational Medicine
6
250ec141-250ec141
10.1126/scitranslmed.3010124
Assessing therapeutic potential of molecules: molecular property diagnostic suite for tuberculosis (MPDSTB)
Anamika Singh Gaur and Anshu Bhardwaj and Arun Sharma and Lijo John and M Ram Vivek and Neha Tripathi and Prasad V Bharatam and Rakesh Kumar and Sridhara Janardhan and Abhaysinh Mori and Anirban Banerji and Andrew M Lynn and Anmol J Hemrom and Anurag Passi and Aparna Singh and Asheesh Kumar and Charuvaka Muvva and Chinmai Madhuri and Chinmayee Choudhury and D Arun Kumar and Deepak Pandit and Deepak R Bharti and Devesh Kumar and ER Azhagiya Singam and Gajendra PS Raghava and Hari Sailaja and Harish Jangra and Kaamini Raithatha and Karunakar Tanneeru and Kumardeep Chaudhary and M Karthikeyan and M Prasanthi and Nandan Kumar and N Yedukondalu and Neeraj K Rajput and P Sri Saranya and Pankaj Narang and Prasun Dutta and R Venkata Krishnan and Reetu Sharma and R Srinithi and Ruchi Mishra and S Hemasri and Sandeep Singh and Subramanian Venkatesan and Suresh Kumar and Uca Jaleel and Vijay Khedkar and Yogesh Joshi and G Narahari Sastry
Abstract Molecular Property Diagnostic Suite () is a web tool ( http://mpds.osdd.net ) designed to assist the in silico drug discovery attempts towards Mycobacterium tuberculosis (Mtb). tool has nine modules which are classified into data library (1–3), data processing (4–5) and data analysis (6–9). Module 1 is a repository of literature and related information available on the Mtb. Module 2 deals with the protein target analysis of the chosen disease area. Module 3 is the compound library consisting of 110.31 million unique molecules generated from public domain databases and custom designed search tools. Module 4 contains tools for chemical file format conversions and 2D to 3D coordinate conversions. Module 5 helps in calculating the molecular descriptors. Module 6 specifically handles QSAR model development tools using descriptors generated in the …
Journal of Chemical Sciences
129
515-531
https://link.springer.com/article/10.1007/s12039-017-1268-4
Investigating the Role of Site Specific Synonymous Variation in Disease Association Studies
A Bhardwaj
Synonymous codon changes may not always be neutral indicating their significance in disease association studies, which is almost always overlooked. Synonymous substitutions may affect protein-folding rates leading to protein misfolding and aggregation. Genome wide analysis of 2301 mitochondrial genomes is performed to evaluate the significance of synonymous codons in disease association studies. The analysis revealed usage of rare codons at several sites in mitochondrial genes with rare codon usage higher for hydrophobic amino acids. The analysis suggests that variation data in association studies should be analyzed using site-specific codon usage values to infer the potential phenotypic impact of synonymous changes.
Mitochondrion
10.1016/j.mito.2013.12.005
Collaborative Tools to Accelerate Neglected Disease Research: Open‐Source Drug Discovery Model
Anshu Bhardwaj and Vinod Scaria and Zakir Thomas and Santhosh Adayikkoth and Samir K Brahmachari
This chapter contains sections titled: Introduction Semantic Web‐based Portal to Link Mind and Machines Description of the Portal: Collaborative Workspaces Social Networking for Research Moving Forward: Future of Virtual Collaborative Research References
Collaborative Computational Technologies for Biomedical Research
321-334
10.1002/9781118026038.ch20
FROG-Fingerprinting Genomic Variation Ontology
E Abinaya and Pankaj Narang and Anshu Bhardwaj
Genetic variations play a crucial role in differential phenotypic outcomes. Given the complexity in establishing this correlation and the enormous data available today, it is imperative to design machine-readable, efficient methods to store, label, search and analyze this data. A semantic approach, FROG: “FingeRprinting Ontology of Genomic variations” is implemented to label variation data, based on its location, function and interactions. FROG has six levels to describe the variation annotation, namely, chromosome, DNA, RNA, protein, variations and interactions. Each level is a conceptual aggregation of logically connected attributes each of which comprises of various properties for the variant. For example, in chromosome level, one of the attributes is location of variation and which has two properties, allosomes or autosomes. Another attribute is variation kind which has four properties, namely, indel, deletion, insertion, substitution. Likewise, there are 48 attributes and 278 properties to capture the variation annotation across six levels. Each property is then assigned a bit score which in turn leads to generation of a binary fingerprint based on the combination of these properties (mostly taken from existing variation ontologies). FROG is a novel and unique method designed for the purpose of labeling the entire variation data generated till date for efficient storage, search and analysis. A web-based platform is designed as a test case for users to navigate sample datasets and generate fingerprints. The platform is available at http://ab-openlab.csir.res.in/frog.
PloS one
10
e0134693
10.1371/journal.pone.0134693
Resources, challenges and way forward in rare mitochondrial diseases research
Neeraj Kumar Rajput and Vipin Singh and Anshu Bhardwaj
Over 300 million people are affected by about 7000 rare diseases globally. There are tremendous resource limitations and challenges in driving research and drug development for rare diseases. Hence, innovative approaches are needed to identify potential solutions. This review focuses on the resources developed over the past years for analysis of genome data towards understanding disease biology especially in the context of mitochondrial diseases, given that mitochondria are central to major cellular pathways and their dysfunction leads to a broad spectrum of diseases. Platforms for collaboration of research groups, clinicians and patients and the advantages of community collaborative efforts in addressing rare diseases are also discussed. The review also describes crowdsourcing and crowdfunding efforts in rare diseases research and how the upcoming initiatives for understanding disease biology …
F1000Research
4
10.12688/f1000research.6208.2
Software Platform for Metabolic Network Reconstruction of Mycobacterium tuberculosis
Samik Ghosh and Yukiko Matsuoka and Yoshiyuki Asai and Hiroaki Kitano and Anshu Bhardwaj and Vinod Scaria and Rohit Vashisht and Anup Shah and Anupam Kumar Mondal and Priti Vishnoi and Kumari Sonal and Akanksha Jain and Priyanka Priyadarshini and Kausik Bhattacharyya and Vikas Kumar and Anurag Passi and Pratibha Sharma and Samir Brahmachari
Tuberculosis (TB) is one of the major infectious diseases still prevailing on this planet. Emergence of drug resistant strains and problems of current treatment regimen warrant need for new drugs for TB. At the same time, economic factor plays a significant role as most patients are in the lowest income bracket of the society. This implies new drugs have to be developed in an innovative manner that allows delivery of drugs at low cost. Drug discovery is in general an expensive and capital-intensive process. A new type of big science is emerging that involves knowledge integration of small sciences as well as coordinating community-based participation. Social dynamics plays critical role in making project successful because open collaboration involves participants with diverse motivations and interests. Thus, proper “social engineering” will play greater role in scientific project planning and management in future …
Systems Biology of Tuberculosis
21
10.1007/978-1-4614-4966-9_2
Systems biology of tuberculosis
Johnjoe McFadden and Dany JV Beste and Andrzej M Kierzek
The book starts with a general introduction into the relevance of systems biology for understanding tuberculosis. This will be followed by several chapters which describe the application of systems biology to various aspects of the study of the pathogen, Mycobacterium tuberculosis, and its interaction with the host. The book provides the reader with an account of how the new science of systems biology is providing novel insights into the ancient scourge of tuberculosis. It will also describe how systems biology can be applied to the control of tuberculosis, including the development of new treatments, vaccines and diagnostics.
http://books.google.com/books?hl=en&lr=&id=TsqSUIMHLmgC&oi=fnd&pg=PR5&dq=info:mjZsRuWbj7sJ:scholar.google.com&ots=RC1kZsmudN&sig=KwjLKvaAwxqoN4a1eQx0MZr9TmE
Open Source Drug Discovery: A Global Collaborative Drug Discovery Model for Tuberculosis
ANSHU Bhardwaj and VINOD Scaria and DEBLINA Patra
The sequencing of the Human and other microbial genomes created stir in the scientific community with the promise to make a remarkable difference to healthcare. Despite the fact that the genome sequence of mycobacterium is available to the scientific community for more than ten years, no effective therapy/drug has been discovered to cure all types of tuberculosis. Although, the big pharmaceutical enterprises have made a commendable contribution to the discovery of drugs for several diseases yet the initiatives for the discovery and development of drugs for infectious diseases such as tuberculosis are sadly lacking. Out of 1,556 new chemical entities marketed worldwide, only 3 were for TB between 1975 and 20041.
Science and Culture
1
22-26
10.1016/j.tube.2011.06.004
Personalized cancer medicines
Anshu Bhardwaj
Over 100 different types of cancers afflict the human population. This large family of diseases is united by a common theme—abnormal cell growth that has the potential to spread across the body. Cancer is treated with a combination of approaches including chemotherapy, radiation, surgery, hormonal therapy, targeted therapy, and palliative care. The selection of the treatment depends on the cancer type, stage, and tissue (s) affected. Some of these therapies are relatively nonspecific, such as chemotherapy, which acts by killing cells that divide rapidly such as cancer cells. Targeted therapy, on the other hand, works on specific molecular differences between cancer and normal cells for better efficacy and reduced toxicity. However, high intertumor heterogeneity is a major hurdle in applying therapeutic targeted agents to treat most cancer patients.High-throughput sequencing technologies are enabling molecular …
Science Translational Medicine
7
280ec48-280ec48
10.1126/scitranslmed.aaa9872
A molecular patch for DMD
Anshu Bhardwaj
Antisense oligonucleotides (AONs)—small DNA fragments used to mask exons so that they are skipped during translation—serve as a sort of molecular patch. This method of exon skipping is currently being tested in clinical trials for treating neuromuscular disorders by preventing exons with nonsense mutations from stalling translation. However, for diseases where whole-body treatment is needed, the current AONs show limited success due to poor tissue uptake and insufficient therapeutic efficacy.In the present study, the Goyenvalle et al. have designed a new AON, tricyclo-DNA (tcDNA), with improved pharmacological properties and uptake by many tissues after systemic administration in mouse models of Duchenne muscular dystrophy (DMD). DMD, an X-linked recessive form of dystrophy, is caused by mutations in the dystrophin gene, which functions to stabilize and protect muscle fibers. Nonsense mutations …
Science Translational Medicine
7
274ec24-274ec24
10.1126/scitranslmed.aaa8311
Evaluating the Association of Mitochondrial SNP Haplotypes with Disease Phenotypes using a Novel in silico Tool E-MIDAS
Anshu Bhardwaj and Shrish Tiwari
Results of association studies using individual single nucleotide polymorphisms (SNPs) or SNP-haplotypes have been inconsistent. Possible reasons could be attributed to poor experimental design, generalization of results from a single population or inappropriate choice of markers. Here we explore the possibility that the sequence context of a SNP may be responsible for its poor association with the phenotype. An analysis of the Human_MitBASE data helped in the prediction of association between SNP haplotypes with disease phenotypes. A novel computational tool E-MIDAS was developed to automate this analysis. Based on our results, we propose omission of SNPs in CpG dinucleotides which have a mutation predisposing flank and those present at sites of recurrent mutation, from association studies.
9th International Conference on Information Technology (ICIT'06)
17-20
10.1109/icit.2006.53
RepTB: a gene ontology based drug repurposing approach for tuberculosis
Anurag Passi and Neeraj Kumar Rajput and David J Wild and Anshu Bhardwaj
Tuberculosis (TB) is the world’s leading infectious killer with 1.8 million deaths in 2015 as reported by WHO. It is therefore imperative that alternate routes of identification of novel anti-TB compounds are explored given the time and costs involved in new drug discovery process. Towards this, we have developed RepTB. This is a unique drug repurposing approach for TB that uses molecular function correlations among known drug-target pairs to predict novel drug-target interactions. In this study, we have created a Gene Ontology based network containing 26,404 edges, 6630 drug and 4083 target nodes. The network, enriched with molecular function ontology, was analyzed using Network Based Inference (NBI). The association scores computed from NBI are used to identify novel drug-target interactions. These interactions are further evaluated based on a combined evidence approach for identification of …
Journal of cheminformatics
10
24
10.1186/s13321-018-0276-9
Resources, challenges and way forward in rare mitochondrial diseases research [v1; ref status: indexed, http://f1000r. es/54x]
Anshu Bhardwaj and Neeraj Kumar Rajput and Vipin Singh
Over 300 million people are affected by about 7000 rare diseases globally. There are tremendous resource limitations and challenges in driving research and drug development for rare diseases. Hence, innovative approaches are needed to identify potential solutions. This review focuses on the resources developed over the past years for analysis of genome data towards understanding disease biology especially in the context of mitochondrial diseases, given that mitochondria are central to major cellular pathways and their dysfunction leads to a broad spectrum of diseases. Platforms for collaboration of research groups, clinicians and patients and the advantages of community collaborative efforts in addressing rare diseases are also discussed. The review also describes crowdsourcing and crowdfunding efforts in rare diseases research and how the upcoming initiatives for understanding disease biology including analyses of large number of genomes are also applicable to rare diseases.
F1000Research
10.12688/f1000research.6208.2
Resources, challenges and way forward in rare mitochondrial diseases research [version 2; referees: 2 approved]
Neeraj Kumar Rajput and Vipin Singh and Anshu Bhardwaj
Over 300 million people are affected by about 7000 rare diseases globally. There are tremendous resource limitations and challenges in driving research and drug development for rare diseases. Hence, innovative approaches are needed to identify potential solutions. This review focuses on the resources developed over the past years for analysis of genome data towards understanding disease biology especially in the context of mitochondrial diseases, given that mitochondria are central to major cellular pathways and their dysfunction leads to a broad spectrum of diseases. Platforms for collaboration of research groups, clinicians and patients and the advantages of community collaborative efforts in addressing rare diseases are also discussed. The review also describes crowdsourcing and crowdfunding efforts in rare diseases research and how the upcoming initiatives for understanding disease biology including analyses of large number of genomes are also applicable to rare diseases.
F1000Research
10.12688/f1000research.6208.2
Ctrl-Alt-Del: Host-Targeting Anti-Angiogenic Agents as Adjunct Therapy for Tuberculosis
Anshu Bhardwaj
Zebrafish offer an excellent model system to study various biological phenomena because of their small size, human-like developmental pattern, and optical transparency. These parallels can be extended to mycobacterial infection, which is caused by Mycobacterium tuberculosis in humans and Mycobacterium marinum in fish. Fish tuberculosis (TB) mimics many aspects of human TB infection, including granuloma formation. Granulomas, which trap infecting mycobacteria, consist of an organized collection of macrophages with a hypoxic core. In tumors, hypoxic tissue is associated with angiogenesis, but angiogenesis in the context of TB granulomas has remained unexplored.Oehlers et al. harness the zebrafish TB model to examine angiogenesis in the context of mycobacterial infection induced granulomas. Long-term live imaging of infected zebrafish larvae clearly showed the growth of vasculature around sites of …
Science Translational Medicine
6
268ec218-268ec218
10.1126/scitranslmed.aaa3463
Cholesterol Therapy That’s Not Chopped Liver
Anshu Bhardwaj
Here’s some extra motivation to put down that bag of chips. Although it’s common knowledge that excess alcohol consumption can harm your liver, a high-fat (HF) diet can lead to liver disease as well. Nonalcoholic fatty liver disease (NAFLD) is a condition where excess fat (triglycerides) accumulates in the liver. NAFLD comprises a spectrum of hepatic disorders in people with little or no alcohol consumption and is recognized as major health concern globally. Presently, there is no standard treatment available to address NAFLD; current therapy is limited mainly to changes in nutrition and lifestyle.Ezetimibe (EZ) is used in the clinic to treat hypercholesteremia and acts by reducing cholesterol and liver steatosis. Cholesterol reduction takes place by inhibition of Niemann-Pick C1 Like 1–mediated cholesterol absorption at the brush border of the intestine and liver. Therefore, Wang et al. further examined the effects of …
Science Translational Medicine
6
262ec193-262ec193
http://stm.sciencemag.org/content/6/262/262ec193.short
Synthetic Lethality: Drug Repurposing with a Difference
Anshu Bhardwaj
β-Lactam is a core skeleton of several potent antibiotics, such as penicillins and carbapenems, that act by inhibiting cell-wall biosynthesis. Intriguingly, most β-lactams are ineffective against Mycobacterium tuberculosis (Mtb). In order to decipher the genetic determinants of this antibiotic resistance, Lun et al. used a screen, called gene-compound synthetic lethality (GCSL), which identified mutations in single genes that caused cell death in the presence of β-lactams (the compound). The authors screened a library of 2,921 mutants of Mtb against imipenem, a β-lactam antibiotic. Mutations in 74 Mtb genes displayed effective inhibition in presence of imipenem. These 74 genes belonged to several different pathways primarily associated with cell-wall biosynthesis. Lun et al. observed that mutant strains of Mtb selected from GCSL screens were more susceptible to imipenem than were wild-type strains. The authors then …
Science Translational Medicine
6
256ec167-256ec167
10.1126/scitranslmed.3010415
"Antigenomic" RNA as a Therapeutic Tool for Mitochondrial Diseases
A Bhardwaj
Mitochondria, commonly known as the powerhouse of the cell, carries its own circular genome, mitochondrial DNA (mtDNA)(16.5 kb). Point mutations in mtDNA have been reported to cause a variety of clinical disorders, which have been attributed to the involvement of mitochondria in several metabolic pathways, often resulting in multisystemic neuromuscular defects such as dystonia, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), and MERRF (myoclonic epilepsy with ragged red fibers). However, in a cell, both normal and mutated mtDNA coexist—a phenomenon called heteroplasmy—and the severity of the pathogenic effect is dependent on the ratio of mutated and normal mtDNA. The normal function of mitochondria can be rescued by shifting the level of heteroplasmy. Various strategies have been proposed to address mtDNA mutations, but with very limited success.In a …
Sci Transl Med
6
232ec66
10.1126/scitranslmed.3009247
Predictive Sciences for Drug Discovery
Geetha Sugumaran and Prasun Dutta and S Ramachandran and David Wild and Tom L Blundell and Anshu Bhardwaj
Dissecting the Enigma of Mycobacterium tuberculosis Pathogenesis
A Bhardwaj
The causal organism of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), is a slow-growing yet very successful pathogen. One characteristic of Mtb that leads to this success is nonreplicating persistence (NRP), which is a reflection of growth arrest and a major contributor to the development of chronic TB infections and drug resistance. Mtb adapts to the changing physiology of the host, which allows it to persist in a human macrophage microenvironment otherwise not suitable for microbial colonization. Considering the complex nature of Mtb infection, molecular understanding of the host-pathogen interactions is imperative to address this global scourge.The study by Abramovitch et al. reports that Mtb buffers its cytoplasmic pH in the acidic environment of the macrophage through a mechanism influenced by host-associated carbon sources and transcriptional remodeling. It has been shown that in rich medium, Mtb …
Science Translational Medicine
6
10.1126/scitranslmed.3009802
Reactive Species Contribute to Antibiotic-Mediated Killing
A Bhardwaj
Antibiotics are designed to target bacteria selectively without damaging host cells. Reactive oxygen species (ROS), however, are more like berserkers. Although ROS are products of normal cellular metabolism, they contribute to oxidative damage against both microbial and host cells. ROS have been implicated in antibiotic-mediated lethality, but the mechanisms underlying this contribution remain unclear. The report by Dwyer et al. proposes a direct role of altered metabolism, respiration, and homoeostatis in ROS-mediated antibiotic lethality.The authors estimated the production of ROS under antibiotic treatment by means of in vivo quantification of ROS on a diverse panel of fluorescent dyes with three different classes of antibiotics: β-lactams, aminoglycoside, and flouroquinolone. Treatment by different antibiotic classes induced different levels of ROS, indicating multiple routes of ROS generation. It was further …
Science Translational Medicine
6
238ec92
10.1126/scitranslmed.3009409
Open access Mycobacterium tuberculosis clone repository: a community resource by OSDD members
Swati Subodh* R. S. Santhosh and Amit Tuteja and Soumashree Basu
We realize that it is imperative to esta blish a centralized repository of Mtb gene clones, which would serve as a re source for researchers working on the OSDD platform, and for those working on various other aspects of TB biology. Using homogenous starting material for any type of downstream experiments will allow comparison of data generated across various laboratories and also ensure re producibility, which is often a matter of concern in drug discovery research. Under the'Connect to Decode'orC2D collaborative programme of the OSDD, a comprehensive re-annotation of the Mtb genome was undertaken2. Sys tems-level approach was employed for identification of potential drug targets in Mtb. This was accomplished through an on-line collaborative approach which successfully generated the most compre hensive protein-protein functional inter action map and reactome of Mtb}. Experimental validation of …
Current Science
105
1342-1345
http://scholar.google.com/scholar?cluster=18190291389313883675&hl=en&oi=scholarr
MtBrowse: An integrative genomics browser for human mitochondrial DNA
Vipin Singh, Bani Jolly, Neeraj K. Rajput, Sayan Pramanik, Anshu Bhardwaj
Mitochondrion
DOI: 10.1016/j.mito.2019.02.003
Data-driven Systems Level Approaches for Drug Repurposing: Combating Drug Resistance in Priority Pathogens
Anurag Passi, Bani Jolly, Tina Sharma, Ashma Pandya, Anshu Bhardwaj
eBook ISBN: 9780128163771