1. CZ5225 Methods in Computational Biology Lecture 6: Drug resistance mutations and model developments CZ5225 Methods in Computational Biology

2. Outline What is the drug resistance? Example of Drug Resistance Mutations. Prediction of drug resistant mutations. –The Needs –Methods Structure based Sequence based –Statistical learning methods –Simple rules

3. CZ5225 Methods in Computational Biology What is the drug resistance? Organisms are said to be drug-resistant when drugs meant to neutralize them have reduced effect or even no effect. Main cause of drug fail during the treatment of infectious disease, cancers (chemotherapy) Main cause of the drug resistance: –Mutation in drug-interacting disease proteins(genetic resistance) –Development of alternative disease related pathway

4. CZ5225 Methods in Computational Biology Example of Drug Resistance Mutations HIV-1 Protease mutations (could be quickly developed) Integrase mutations …… Henderson L. and Arthur L. 2005. NIH AIDS Research and Reference Reagent Program

5. CZ5225 Methods in Computational Biology The needs for drug resistance mutations prediction The molecular analysis of drug resistance mechanismsThe molecular analysis of drug resistance mechanisms Design new agents to against resistant strainsDesign new agents to against resistant strains Guide the clinical regimen to fight with diseaseGuide the clinical regimen to fight with disease

6. CZ5225 Methods in Computational Biology Methods for mechanistic study and prediction of resistance mutations Structure-based approachesStructure-based approaches –molecular modeling approach –evolutionary simulation model –neural network model Sequence-based approaches –Statistical learning methods Neural networks (NN) (classification, association, regression) Support vector machines (SVM) )(classification, regression) Decision tree (DT) –Simple rules (HIVdb, HIValg, ARS, and VGI etc)

7. CZ5225 Methods in Computational Biology Methods for mechanistic study and prediction of resistance mutations Statistical learning methods –Neural networks (NN) (classification, association, regression) –Support vector machines (SVM) )(classification, regression) –Decision tree (DT)

8. CZ5225 Methods in Computational Biology Methods for mechanistic study and prediction of resistance mutations –Simple rules Protein Mutations Drugs Genotypic Phenotypic Penalty

9. CZ5225 Methods in Computational Biology Methods for mechanistic study and prediction of resistance mutations –Simple rules Penalty susceptible potential low-level resistance low-level resistance Intermediate resistance high-level resistance

10. CZ5225 Methods in Computational Biology Methods -Simple rules Scoring Matrix -- example

11. CZ5225 Methods in Computational Biology A Question How to develop the Scoring Matrix ? Statistics derived rules