Transcript Slide 1
The Mycobacterium tuberculosis SysBorg Life from the perspective of the pathogen Questions in Tuberculosis Latent stage Latency? Express antivirulence; Hide Battle lost Pi N M. tuberculosis entering a macrophage Subvert Host signalling; live within the enemy Find surface receptors and enter; Friendship Pathogen GENOME FINALIZATION OF ORFs (CONSIDER EXPRESSION ISSUES) ORFs PROTEIN PRODUCED CLONING PROTEIN SEQUENCES TARGET VALIDATION SIMILARITY SEARCH ALGORITHMS BLAST, PLHoST, BLASTCLUST,… FUNCTION PREDICTION IN SILICO TARGET ASSESSMENT BIOCHEMICAL ASSAY BIOPHYSICAL ASSAY TARGET SELECTION ALGORITHMS INVARIANT PEPTIDES, HIGH COST, USING M. tuberculosis PATHOGEN(+) AND HUMAN(-), PDB, SysBorg SURFACE PREDICTION STEPS TO DRUG DISCOVERY Pathogen GENOME FINALIZATION OF ORFs (CONSIDER EXPRESSION ISSUES) ORFs CLONING PROTEIN PRODUCED PROTEIN SEQUENCES SURFACE LOCALIZATION ALGORITHMS PSORT, SPAAN, MAAP,… IN SILICO CANDIDATE ASSESSMENT SURFACE PREDICTION USING M. tuberculosis FILTERING ALGORITHMS SysBorg EPITOPE PREDICTION, ALLERGENS, ANTIGENIC REGIONS, TRANSMEMBRANE REGIONS PATHOGEN(+) AND HUMAN(-), PDB USE ANIMAL MODELS STEPS TO VACCINE DISCOVERY The Events Chairman, proposes a networked initiative for tuberculosis Combination query samples generated applying boolean and arithmetic operators Scientists & students collect curated data in structured format Co-ordinator assigned. Partnership with SilicoGene, Industry established A Flexible architecture proposed, where the numbers of Fields, Tables and Units were made flexible Windows version Data Plugged in to the platform A first version of structure of SysBorg platform prepared. This had fixed number of Fields A Brainstorming session was held LINUX version also developed Construction of M. tuberculosis SysBorg is a Mega Project Networking of expert scientists at the national level HK RC SKB DD BS BKM CNM BP RR VB M. tuberculosis SysBorg SR MB BKM YS GPSR SG SM SC RS M. tuberculosis SysBorg : A systems Biology platform for infectious diseases using Systems Biology of whole organism How does Latency arise Fumarate What does M.tb do during infection ATP How does M.tb infect How is the pathogen cleared Metabolic and Signalling Network ( CSIR Task force Network for in silico drug target discovery ) IMTECH CDRI IICB Other partners ACBR VPCI NII RRLJ Activity structuring Blocks annotation drugs geneexpress hostpatho strainpoly pathways Units Tables Tables Tables Tables Tables Tables Tables Tables Tables Tables Tables Tables A Seventh Block administration Payments Certification from Scientists Reports consolidation Chasing Intellectual Property Rights Business Development issues Drafting agreements and signing Data structuring Decide on Primary Key GI Number? Rv Number? For Drug Block? In the Brain storming session scientists elected to use Rv Number following TubercuList created by Stewart Cole’s group but also provide mapping to GI numbers Anticipated Difficulties – Forced Redundancies Several drugs or small molecules for each protein Each drug has several attributes (Fields) Creation of Redundant entries – Records with repetition of Rv nos. Several immunochemical data for each protein antigen data Each study has different facets of immunochemical data Creation of Redundant entries – Records with repetition of Rv nos. Another difficulty – Many published reports in the pre-genome sequence era did not use ORF nos. or ORF ids Mapping with calculated molecular weight is risky Due to (1) Experimental Errors? (2) Whether they were whole proteins or degraded or processed? Caveats We will have a Redundant Database with replicate entries Each entry mapped to a singular PubMed ID is possible. In case of drugs, several PubMed IDs will come. We will never be able to use many data available in the literature Result of a query Multiple data on some ORFs and little or no data on many ORFs Antigens Table 500 450 400 350 300 250 200 150 100 50 0 1 Total 2 Non-redundant Post Genome era of M. tuberculosis Should experiments be repeated – If yes, then who will fund? If no, then how do we benefit? We just have to live with it! annot 4 Basic questions to be pursued: How does a pathogen infect its host? How does latency arise? What is the process of infection? How pathogens are cleared by our immune system? ABCPred BetaBarrelOuterMembraneProteins CDC1551HorizontalTransfer DNABinder DuplicatedGenes EssentialGene GeneFunctionPredictionOfIntergenicRegion InterdomInteractions InvariantSignatures Literature IN OPEN SOURCE PORTAL OperonMapTable (OPEN SOURCE DRUG DISCOVERY) Operons USE R, BIOCONDUCTOR, WIKI/TWIKI drugs ORFFunctions OrthologousGenes FirstLineDrugs PrintsPatterns FirstLineDrugsStructureActivity PrositePatterns SecondLineDrugs PsortSubcellularLocalisation DrugResistance RNABinder NewDrugEntities Rv2GI DrugFailures RvHorizontalTransfer DrugResponseRNAProtein UnfoldedandFolded TDRTargets geneexpress MtbStrainWiseExpressionZScores CodonAdaptationIndex CodonAdaptationIndexCDC1551 CodonAdaptationIndexH37Ra ExperimentallyValidatedEssentialGenes GenesRequiredForOptimalGrowth GQuadraplexIntergenic3 4 Basic questions to be pursued: How does a pathogen infect its host? How does latency arise? What is the process of infection? How pathogens are cleared by our immune system? IN OPEN SOURCE PORTAL (OPEN SOURCE DRUG DISCOVERY) USE R, BIOCONDUCTOR, WIKI/TWIKI GeneticComparison NonEssentialGenes GQuadraplexIntergenic GQuadraplexIntragenic1 Gquadraplexintragenic GQuadraplexRegulatory2 GQuadraplexRegulatory HighProbabilityOfEssentialGenes IntergenicRegionsHighExpressionGeneE IntergenicRegionsHighExpressionP miRNABindingSites hostpatho Antigens HostMimicry MtbPersistance SurfaceAdhesion VaccineCandidatesPad pathways NewTransporter PathwayReaction STKinasesPhosphatases GenomeScaleMetabolicReactionNetwork 4 Basic questions to be pursued: How does a pathogen infect its host? How does latency arise? What is the process of infection? How pathogens are cleared by our immune system? IN OPEN SOURCE PORTAL (OPEN SOURCE DRUG DISCOVERY) USE R, BIOCONDUCTOR, WIKI/TWIKI strainpoly proteininteract ProteinInteraction ProteinProteinInteractionValues InDelintergenic InDelintragenic InterspersedRepetitive SNPintragenic SNPintergenic RvMIRUGenePosition TransposonMutantsFinal Targeting Microbial Surface Proteins for therapeutics Attachment mediated by adhesins Colonization and pathogenesis Drug OR Antibody bind to adhesins and abrogate binding of pathogens to host cell receptors FOUR CLASSES OF ADHESINS ARE KNOWN IN PATHOGENS All proteins of M. tuberculosis 3997 Give me proteins with Pad >= 0.7 201 How many proteins are in Antigens table? How many proteins have no match with Human proteins 15 57 Amit Sinha, Ayush Raman, Archana Pan, B.K.Malik, Balvinder Singh, Beena Pillai, Bhanot Priyamwada Sinha,Chabinath N. Mandal, Charu Kapil Richa, Chitra Dutta, Chitra Dutta, Debasis Dash, Debojyoti Chakraborty, Faraz Alam Ansari, G.P. Singh, Gajendra Pal Singh Raghava, Gargi Guhathakurta, Ipsita Chanda, Manoj Hariharan, Mekapati Bala Subramanyam, Mridula Bose, Mudgal Haymanti, Muthiah Gnanamani, Nanda Ghoshal, Pallavi Sarmah, Rakesh K. Sharma, Ranjan Basu, Ravishankar Ramachandran, Rupanjali Chaudhuri, Srinivasan Ramachandran*, Sabyasachi Das, Samir K. Brahmachari, Sandip Paul, Sanjib Chatterjee, Shantanu Chowdhury, Simone Gupta, Souvik Maiti, Subhagata Ghosh, Suchir Arora, Sudipto Saha, Sumit Deb, Vani Brahmachari, Vikram Kumar, Vinod Scaria, Yasha Bhasin, Yogendra Singh