Simultaneously Targeting Multiple Drug-Resistant Variants with Optimally Small Drug Cocktails: Application and Analysis of Novel Methods

Abstract

Target mutation is a key problem in drug design. High mutational variation of a drug target leads to resistance: drugs which may have originally functioned as inhibitors lose potency because structural changes in the target lead to losses in binding affinity. One way to approach this problem is through the use of drug cocktails. Using integer-programming and physics-based energy functions, we can select an optimally small cocktail from the combinatorial space of possible drugs built from molecular fragments. This computational framework has been presented in previous work by Radhakrishnan and Tidor (J. Chem. Inf. Model., 2008). Current investigations involve analyzing and improving the efficiency of this method and applying it to rapidly varying targets in the HIV-1 system.