title: Theoretical studies on the molecular basis of HIV-1RT/NNRTIs interactions.
abstract: Molecular dynamics simulations (MD) of the human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) complexed with the four non-nucleoside reverse transcriptase inhibitors (NNRTIs): efavirenz (EFV), emivirine (EMV), etravirine (ETV) and nevirapine (NVP), were performed to examine the structures, binding free energies and the importance of water molecules in the binding site. The binding free energy, calculated using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), was found to decrease in the following order: EFV ~ ETV > EMV > NVP. The decrease in stability of the HIV-1 RT/NNRTI complexes is in good agreement with the experimentally derived half maximal inhibitory concentration (IC(50)) values. The interaction energy of the protein-inhibitor complexes was found to be essentially associated with the cluster of seven hydrophobic residues, L100, V106, Y181, Y188, F227, W229 and P236, and two basic residues, K101 and K103. Moreover, these residues are considered to be the most frequently detected mutated amino acids during treatment by various NNRTIs and therefore, those most likely to have been selected in the population for resistance.
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok, Thailand.
authors.forename: Panita
authors.initials: P
authors.lastname: Decha
authors.forename: Pathumwadee
authors.initials: P
authors.lastname: Intharathep
authors.forename: Thanyarat
authors.initials: T
authors.lastname: Udommaneethanakit
authors.forename: Pornthep
authors.initials: P
authors.lastname: Sompornpisut
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
authors.forename: Peter
authors.initials: P
authors.lastname: Wolschann
authors.forename: Vudhichai
authors.initials: V
authors.lastname: Parasuk
mesh_terms: D000480:Alkynes; D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D048588:Benzoxazines / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D003521:Cyclopropanes; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000187:drug effects; D019829:Nevirapine / Q000378:metabolism* / Q000494:pharmacology; D009570:Nitriles; D011485:Protein Binding; D011487:Protein Conformation; D011724:Pyridazines / Q000378:metabolism* / Q000494:pharmacology; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013816:Thermodynamics; D014498:Uracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D000480:Alkynes; D000596:Amino Acids; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D014867:Water; C451734:etravirine; D014498:Uracil; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C098320:efavirenz; C083858:emivirine