title: Molecular mechanics PBSA ligand binding energy and interaction of Efavirenz derivatives with HIV-1 reverse transcriptase.
abstract: In order to evaluate the properties of several HIV-1 reverse transcripase(RT) inhibitors, Efavirenz (SUSTIVA) and a set of its derivatives (benzoxazinones) have been placed into the nonnucleoside analogue binding site of the enzyme by molecular docking. The resulting geometries were used for a molecular dynamics simulation and binding energy calculations. The enzyme-inhibitor binding energies were estimated from experimental inhibitory activities (IC90). The correlation of the predicted and experimental binding energies were satisfactory acceptable as indicated by r2 = 0.865. Based on MD simulations, the obtained results indicate that the tight association of the ligand to the HIV-1 RT binding pocket was based on hydrogen bonding between Efavirenz's N1 and the oxygen of the backbone of Lys 101, with an estimated average distance of 1.88 A. Moreover, electrostatic interaction was mainly contributed by two amino acid residues in the binding site; Lys 101 and His 235. MD simulations open the possibility to study the reaction of the flexible enzyme to those substances as well as the overall affinity.
authors.affiliation: Institute for Theoretical Chemistry and Structural Biology, University of Vienna, Waehringer Strasse 17, Vienna 1090, Austria. philipp.weinzinger@tbi.univie.ac.at
authors.forename: Philipp
authors.initials: P
authors.lastname: Weinzinger
authors.forename: Supa
authors.initials: S
authors.lastname: Hannongbua
authors.forename: Peter
authors.initials: P
authors.lastname: Wolschann
mesh_terms: D000272:Adipates / Q000737:chemistry*; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003521:Cyclopropanes; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D006860:Hydrogen Bonding; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D010078:Oxazines / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D013386:Succinates / Q000737:chemistry*
chemical_list: D000272:Adipates; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D008024:Ligands; D010078:Oxazines; D013386:Succinates; C437084:poly(tetramethylene succinate-co-tetramethylene adipate); D006639:Histidine; D054303:HIV Reverse Transcriptase; C098320:efavirenz; D008239:Lysine