Novel radial distribution function approach in the study of point mutations: the HIV-1 protease case study

Abstract

Background: Mutations are one of the engines of evolution. Under constant stress pressure, mutations can lead to the emergence of unwanted, drug-resistant entities. Methodology: The radial distribution function weighted by the number of valence shell electrons is used to design quantitative structure–activity relationship (QSAR) model relating descriptors with the inhibition constant for a series of wild-type HIV-1 protease inhibitor complexes. The residuals of complexes with mutant HIV-1 protease were correlated with the energy of the highest occupied molecular orbitals of the residues introduced to enzyme via point mutations. Conclusion: Successful identification of residues Ile3, Asp25, Val32 and Ile50 as the one whose substitution influences the inhibition constant the most, demonstrates the potential of the proposed methodology for the study of the effects of point mutations.