Multiple drugs and multiple targets: an analysis of the electrostatic determinants of binding between non-nucleoside HIV-1 reverse transcriptase inhibitors and variants of HIV-1 RT.

We present a systematic, computational analysis of the electrostatic component of binding of three HIV-1 RT inhibitors-nevirapine (NVP), efavirenz (EFV), and the recently approved rilpivirine (RPV)-to wild-type (WT) and mutant variants of RT. Electrostatic charge optimization was applied to determine how suited each molecule's charge distribution is for binding WT and individual mutants of HIV-1 RT. Although the charge distributions of NVP and EFV are rather far from being optimal for tight binding, RPVs charge distribution is close to the theoretical, optimal charge distribution for binding WT HIV-1 RT, although slight changes in charge can dramatically impact binding energetics.