title: Effects of the protonation state in the interaction of an HIV-1 reverse transcriptase (RT) amino acid, Lys101, and a non nucleoside RT inhibitor, GW420867X.
abstract: Interactions between an inhibitor and amino acids from a binding pocket could help not only to understand the nature of these interactions, but also to support the design of new inhibitors. In this paper, we explore the key interaction between a second generation non-nucleoside reverse transcriptase inhibitor (NNRTI), GW420867X, and HIV-1 RT amino acid Lys101 (K101), by quantum mechanical methods. The neutral, protonated, and zwitterionic complexes of GW420867X-K101 were studied. The interaction energies were determined by SCS-MP2/def2-cc-pVQZ, and the electron density was analyzed by natural bond orbital (NBO), atoms in molecules (AIM) and reduced gradient analysis. A large increase in the interaction was observed with the tautomerization of neutral or neutral protonated species. The monomers interact by two medium-strength hydrogen bonds, one partially covalent and another noncovalent. There are some van der Waals intramolecular interactions that are topologically unstable. The nature of the intermolecular interactions was also analyzed using quantitative molecular orbital (MO) theory in combination with an energy decomposition analysis (EDA) based on dispersion-corrected density functional theory (DFT) at BLYP-D/TZ2P.
authors: Departamento de Química, FFCLRP-USP, Av. Bandeirantes, 3900, Ribeirão Preto, SP, Brazil, segalemb@usp.br.
authors: Sérgio E
authors: SE
authors: Galembeck
authors: F Matthias
authors: FM
authors: Bickelhaupt
authors: Célia
authors: C
authors: Fonseca Guerra
authors: Eduardo
authors: E
authors: Galembeck
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D004583:Electrons; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008239:Lysine; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D011789:Quantum Theory; D011810:Quinoxalines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; C402066:GW420867X; D008024:Ligands; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D008239:Lysine