Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok, Thailand.
J Enzyme Inhib Med Chem. 2011 Feb;26(1):29-36. doi: 10.3109/14756360903563393. Epub 2010 Jun 28.
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.
对人类免疫缺陷病毒 1 型逆转录酶(HIV-1 RT)与四种非核苷类逆转录酶抑制剂(NNRTIs):依非韦伦(EFV)、依法韦仑(EMV)、埃替拉韦(ETV)和奈韦拉平(NVP)复合物的分子动力学模拟(MD)进行了研究,以考察结构、结合自由能以及结合部位水分子的重要性。使用分子力学泊松-玻尔兹曼表面积(MM-PBSA)计算的结合自由能按以下顺序降低:EFV~ETV>EMV>NVP。HIV-1 RT/NNRTI 复合物稳定性的降低与实验得出的半数最大抑制浓度(IC(50))值非常吻合。发现蛋白质-抑制剂复合物的相互作用能主要与七个疏水性残基 L100、V106、Y181、Y188、F227、W229 和 P236 以及两个碱性残基 K101 和 K103 的簇有关。此外,这些残基被认为是在各种 NNRTIs 治疗过程中最常检测到的突变氨基酸,因此,它们最有可能在人群中选择产生耐药性。