engleski

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

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 func- tion 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 pro- posed methodology for the study of the effects of point mutations.

drug design ; HIV-1 protease ; inhibitors ; mutations ; QSAR ; radial distribution function ; RDF

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