Lecture 6: Drug resistance mutations and model developments

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

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. 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. 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. The needs for drug resistance mutations prediction • The molecular analysis of drug resistance mechanisms • Design new agents to against resistant strains • Guide the clinical regimen to fight with disease

6. Methods for mechanistic study and prediction of resistance mutations • Structure-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. 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. Penalty Penalty Penalty Penalty Penalty Penalty Penalty Penalty Penalty Penalty Penalty Methods for mechanistic study and prediction of resistance mutations • Simple rules Phenotypic Drugs Protein Mutations Genotypic

9. Penalty Penalty Penalty Penalty Penalty Penalty Penalty Penalty Methods for mechanistic study and prediction of resistance mutations • Simple rules susceptible potential low-level resistance low-level resistance Intermediate resistance high-level resistance

10. Methods -Simple rules • Scoring Matrix -- example

11. A Question • How to develop the Scoring Matrix ? Statistics derived rules