Transcript Lecture 6: Drug resistance mutations and model developments

CZ5225 Methods in Computational Biology
CZ5225 Methods in Computational Biology
Lecture 6: Drug resistance mutations and model
developments
CZ5225 Methods in Computational Biology
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
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
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
CZ5225 Methods in Computational Biology
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
CZ5225 Methods in Computational Biology
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)
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)
CZ5225 Methods in Computational Biology
Methods
for mechanistic study and prediction of resistance mutations
–Simple rules
Phenotypic
Drugs
Protein Mutations
Genotypic
Penalty
Penalty
Penalty
Penalty
Penalty
Penalty
Penalty
Penalty
Penalty
Penalty
Penalty
CZ5225 Methods in Computational Biology
Methods
for mechanistic study and prediction of resistance
mutations
–Simple rules

Penalty
Penalty
Penalty
Penalty
Penalty
Penalty
Penalty
Penalty
susceptible
potential low-level resistance
low-level resistance
Intermediate resistance
high-level resistance
CZ5225 Methods in Computational Biology
Methods -Simple rules
Scoring Matrix -- example
CZ5225 Methods in Computational Biology
A Question
How to develop the Scoring Matrix ?
Statistics derived rules