title: Energetics of mutation-induced changes in potency of lersivirine against HIV-1 reverse transcriptase.
abstract: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy for the treatment of HIV-1. A common problem with the first generation NNRTIs is the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular, K103N and Y181C, which lead to resistance to the entire class of inhibitor. Here we have evaluated the relative affinity of the newly designed NNRTI lersivirine (LRV) against drug-resistant mutations in HIV-1 RT using the molecular mechanics generalized Born surface area (MM-GBSA) method. Eight single and one double mutant variants of RT are considered. Our results are in good agreement with experimental results and yield insights into the mechanisms underlying mutation-induced changes in the potency of LRV against RT. The strongest (54-fold) increase in the dissociation constant is found for the mutant F227C, originating from reduced electrostatic and van der Waals interactions between LRV and RT as well as a higher energetic penalty from the desolvation of polar groups. For the mutants K103N and Y181C only a moderate (2-fold) increase in the dissociation constant is found, due to a balance of opposite changes in the polar solvation as well as the electrostatic and van der Waals interactions between LRV and RT. The dissociation constant is decreased for the Y188C and G190A (2-fold), the M184V (5-fold), and the Y188C/Y188C mutant (10-fold), due to stronger electrostatic interactions between LRV and RT. Our results thus suggest that LRV is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses, which is in agreement with experimental observations.
authors.affiliation: Department of Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.
authors.forename: Parimal
authors.initials: P
authors.lastname: Kar
authors.forename: Volker
authors.initials: V
authors.lastname: Knecht
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics*; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061; D014867:Water; D054303:HIV Reverse Transcriptase