Institute of Microbial Technology, Chandigarh, India Email: raghava@imtech.res.in http://crdd.osdd.net/ Email: raghava@imtech.res.in http://crdd.osdd.net/ http://ww.imtech.res.in/raghava/ http://ww.imtech.res.in/raghava/
Drug/inhibitor/vaccine/ Peptide-Protein Peptide Structure, Disease Diagnostics Interaction docked structure Adaptive Immunity: B-cell, Innate Immunity: Toll-like T-cell Epitope receptors Anti-(bacterial , microbial, Mimotopes for diseases cancer, viral) peptides diagnostics Structure determination: Structure prediction: Peptide/ Natural, non-natural , Natural, non-natural , Proteins modified bonds modified bonds Synthesis: Phase display, Natural bioactive peptides SPSS, Codon Suffeling from metagenomics Mimotopes for B/T epitopes Mimicking of Drug Molecules Size Optimization ADMET: Proteolytic Oral Delivery : Trans. for function/Str. enzymes, Half-life & Adjuvant
Therapeutic Application of Peptides Limitation of Peptides & Challenge for Bioinformaticians Peptide Web Peptide Servers Databases Application of peptides in treating cancer
Therapeutic Application of Biomolecules Peptide based Drugs (Small Molecule, Peptide, Protein) • Anticancer peptides • Antibacterial peptides Peptide for delivering drug • Cell-penetrating peptides • Tumor-homing peptides Peptide as disease diagnostics • Disease specific Mimotopes Epitope/Peptide based Vaccines • T-cell epitopes • B-cell epitopes
Limitation of Peptides & Challenges for Bioinformaticians 1. Peptide Degradation (short half-life) Large peptide degrading enzymes • Hepatic/renal Clearance (liver/kidenys) • 2. Low Oral Bioavailability (injection) 3. High conformational flexibility Environment dependent tertiary structure • Low selectivity • 4. Immunogenicity and antigenicity 5. High cost of production & Storage Modification/glycosylation of peptides •
Important Resources/Databases MHCBN: MHC binding and non-binding peptides CPPsite: Cell penetrating peptides BCIpep: B-cell epitope datbase HMRbase: A database of hormones and their receptors TumorHope: Tumor hoping peptides TumorHPD: Designing of Tumor Homing Peptides CellPPD: Designing of cell penetrating peptides Pepstr: Prediction of Peptide structure AntiCP: Prediction and designing of anticancer peptides
Adaptive Immunity Protective Antigens Bioinformatics Centre Innate Immunity IMTECH, Chandigarh Vaccine Delivery Disease Causing Agents Pathogens/Invaders
Adaptive Immunity Protective Antigens Bioinformatics Centre Innate Immunity IMTECH, Chandigarh Vaccine Delivery Purified Antigen WHOLE Epitopes (Subunit ORGANISM Vaccine) T cell epitope Attenuated
Adaptive Immunity Protective Antigens Bioinformatics Centre Innate Immunity IMTECH, Chandigarh Vaccine Delivery ER TAP Prediction of CTL Epitopes (Cell-mediated immunity)
Adaptive Immunity Protective Antigens Bioinformatics Centre Innate Immunity IMTECH, Chandigarh Vaccine Delivery Prediction of B-Cell Epitopes • BCEpred: Prediction of Continuous B-cell epitopes – Benchmarking of existing methods – Poor performance slightly better than random – Combine all properties and achieve accuracy around 58% – Saha and Raghava (2004) ICARIS 197-204. • ABCpred: ANN based method for B-cell epitope prediction – Extract all epitopes from BCIPEP (around 2400) – 700 non-redundant epitopes used for testing and training – Recurrent neural network – Accuracy 66% achieved – Saha and Raghava (2006) Proteins,65:40-48 • ALGpred: Mapping and Prediction of Allergenic Epitopes – Allergenic proteins – IgE epitope and mapping – Saha and Raghava (2006) Nucleic Acids Research 34:W202-W209 • CBTOPE: Prediction of conformational epitopes
Modelling of Immune System for Designing Epitope-based Vaccines Propred: for promiscuous MHC II binders Adaptive Immunity (Cellular Response) : MMBpred: for high affinity mutated binders T helper Epitopes MHC2pred: SVM based method MHCBN : A database of MHC/TAP binders and non-binders Pcleavage : for proteome cleavage sites Adaptive Immunity TAPpred: for predicting TAP binders (Cellular Response) : Propred1: for promiscuous MHC I binders CTL Epitopes CTLpred: Prediction of CTL epitopes BCIpep: A database of B-cell eptioes; ABCpred: for predicting B-cell epitopes Adaptive Immunity ALGpred: for allergens and IgE eptopes (Humoral HaptenDB: A datbase of haptens Response) :B-cell Epitopes Innate Immunity : PRRDB: A database of PRRs & ligands Pathogen Recognizing Antibp: for anti-bacterial peptides Receptors and ligands Signal transduction in Cytopred: for classification of Cytokines Immune System
Peptide structure prediction • 3D structures of 77 biologically active peptides (9-20 residues) • 3D structures of 77 biologically active peptides (9-20 residues)
Peptide structure prediction Averaged backbone root mean deviation before and Averaged backbone root mean deviation before and after energy minimization and dynamics simulations. after energy minimization and dynamics simulations.
Peptide Web Servers
Peptide Web Servers
Designing of antibacterial stable peptides Scanning of peptides in a protein Submition of multiple peptides
Peptide Resources/Databases
Peptide Web Servers
Designing of therapeutic peptides against cancer Anticancer peptides Peptide inhibitors Designing of Identification of effective anticancer inhibitors against peptides cancer targets Cell Penetrating ? Tumor Homing Peptides Peptides TumorHoPe: CPPsite: Database Database TumorHPD: CellPred: Design Design Peptides Half-life Toxicity of Peptides HLP: prediction in Immuno-, cyto-toxicity intestine Off targets
Peptide Resources/Databases
Peptide Resources/Databases Work in Progress 1. Prediction of CPP 2. Designing CPP 3. Scanning in proteins
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