Rational Approaches for the Design of Effective Human Immunodeficiency Virus Type I Nonnucleoside Reverse Transcriptase Inhibitors

RIBONE S., QUEVEDO, M.A., MADRID M., BRIÑÓN, M.C.

JOURNAL OF CHEMICAL INFORMATION AND MODELING

AMER CHEMICAL SOC

Año: 2011 vol. 51 p. 130 - 138

1549-9596

The binding of several classes of non-nucleoside reverse transcriptase inhibitors(NNRTIs) to wild type (wtRT) and K103N mutant (mRT) human immunodeficiency virus-1(HIV-1) reverse transcriptase is studied using molecular dynamics and energy decompositiontechniques. The ITU, DATA and DAPY NNRTIs studied maintain the hydrogen bond withLys101 during the 3 ns molecular dynamics trajectories. When bound to mRT, all the DAPYsstudied establish hydrogen bonds with Glu138, among these, those of the potent inhibitorsTMC120 and TMC125 are water-mediated. The molecular interactions of the NNRTIs in thebinding pocket are correlated to the drugs? potency. Quantitative free energy analyses show alinear relationship between the van der Waals energetic component and the potency againstwtRT. The molecular basis of the interaction between NNRTIs and RT presented hereprovide quantitative approaches for the design of novel effective anti-HIV drugs.