Target Based Drug Combination Selection
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The presentation outlines an algorithm to identify combinations of drug for a given therapeutic endpoint. The objective is to target different stages of the disease pathway. Chemoinformatics as employed by Ontomine, a US patent pending algorithm is employed for the same.
![Target Based Drug Combination Selection Systems Biology Worldwide Combination Drug ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Methods to find potential Drug Combinations Searching Drug Combination Space Searching potential drugs among set of drugs (N) (binary/ternary combination) requires factorial design to consider all possible combinations ( N C 2 or N C 3 ), however selection process can be optimized by using search algorithms. We have used statistic derived from various parallel analysis (Chemoinformatics analysis by Ontomine, Docking, Gene Expression Network Analysis...) as a deciding criteria to search potential drug/combination. Hypothesis ,[object Object],[object Object],[object Object],[object Object],[object Object],Analysis flow ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Ontomine Analysis Gene Network Analysis Network analysis can reveal many important information about disease mechanism, and it's been used to select target genes for disease. Network can be generated based on gene/protein expression data. Network analysis algorithm focuses on finding small networks, which are easier to interpret and validate. It computes p-values for sub-networks, which helps us in identifying significant subnetworks. This analysis produced list of significant subnetworks. * Network is generated by borrowing information from protein-protein interaction, pathways database. * Network could be generated from Gene expression and/or Protein expression data. Algorithm Comments ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],We have applied novel idea for selection of Drug Combination by integration of ideas from different fields like Chemoinformatics, Structural Informatics, Bioinformatics, and Microarray Data Analysis. Our analytical method was successful in detecting combination drug available in market. ,[object Object],[object Object],[object Object],[object Object],Docking Reverse Docking : Potential binding proteins may be discovered by docking a drug to repository of drug target database. Potential Drug Target Database (PDTD) is used for reverse docking. The objective of this method is to find drug targets. Forward Docking: Docking is performed on few target proteins selected by analysis. The objective of this method is to estimate predicted Ki and understand binding behaviour of Drug. Ontomine transforms the structural information for chemically, biologically or pharmacologically related molecules to a hierarchical schema of functional groups. It discovers patterns in the related schema and predicts biological activity, Toxicity & Side-effect using rules inferred from analyzing the patterns. Target profiling in Ontomine is done by mining Drug Target and BioAssay KnowledgeBase for set of Drugs. Output of Ontomine analysis is set of target protein for particular drug along with confidence level of prediction. Ontomine is also used to generate ADME-Tox profile of drug. Int_score : It is a summary statistic which combines result of various analysis (Ontomine/Docking/Network Analysis). It also considers target specificity, competitive binding, ADME-Tox profile for a given drug or combination Target proteins identified by Ontomine, Docking and Network Analysis are mapped on KEGG disease specific pathways, followed by enrichment analysis for mechanistic understanding of drug and/or drug combination action. Systems Biology Worldwide SBW © A B](https://image.slidesharecdn.com/targetbaseddrugcombinationselection-12579324034371-phpapp01/85/Target-Based-Drug-Combination-Selection-1-320.jpg)
