Chong Youhoon, Borroto-Esoda Katyna, Furman Phillip A, Schinazi Raymond F, Chu Chung K
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, USA.
Antivir Chem Chemother. 2002 Mar;13(2):115-28. doi: 10.1177/095632020201300205.
In order to understand molecular mechanism of antiviral drug resistance of HIV-1 reverse transcriptase (RT) as well as potent antiviral activity of 2,6-diaminopurine dioxolane (DAPD) [prodrug of (-)-beta-D-dioxolane guanine (DXG)] against drug-resistant RTs, molecular modelling studies of three structurally distinct nucleoside RT inhibitor (NRTI)-triphosphates (TP) [zidovudine (AZT)-TP, lamivudine (3TC)-TP and DXG-TP] complexed with the wild-type (WT) and mutated RT were conducted. The computational analyses indicated that the antiviral activity and the calculated relative binding energy of the RT inhibitor triphosphates can be correlated, and the minimized structures gave information on the molecular mechanism of drug resistance conferred by mutations. The interactions between the NRTI-TP and adjacent amino acid residues (Lys65, Lys70, Arg72, Tyr115 and/or Gln151) played important roles in stabilizing the enzyme-inhibitor complex. Particularly, Arg72 was found to stabilize the dioxolane and oxathiolane sugar moiety through hydrogen bonding, which was responsible for favourable binding affinity of DXG-TP to AZT- as well as 3TC-resistant mutants. The conformational changes in these amino acid residues caused by mutation always affected the changes in the tertiary structures of enzyme-inhibitor complexes through either closing or opening the gap between the fingers and palm domains. The enzyme-inhibitor complexes with good binding affinity showed tight binding modes by closing the gap between the two domains, whereas weak inhibitors gave open and loose complexes.
为了了解HIV-1逆转录酶（RT）抗病毒耐药性的分子机制以及2,6-二氨基嘌呤二氧戊环（DAPD）[（-）-β-D-二氧戊环鸟嘌呤（DXG）的前体药物]对耐药RTs的强效抗病毒活性，对三种结构不同的核苷类逆转录酶抑制剂（NRTI）-三磷酸酯（TP）[齐多夫定（AZT）-TP、拉米夫定（3TC）-TP和DXG-TP]与野生型（WT）和突变型RT复合进行了分子模拟研究。计算分析表明，RT抑制剂三磷酸酯的抗病毒活性与计算得到的相对结合能具有相关性，最小化结构提供了有关突变导致耐药性的分子机制的信息。NRTI-TP与相邻氨基酸残基（Lys65、Lys70、Arg72、Tyr115和/或Gln151）之间的相互作用在稳定酶-抑制剂复合物中起重要作用。特别地，发现Arg72通过氢键稳定二氧戊环和氧杂硫杂环戊烷糖部分，这是DXG-TP对AZT-以及3TC耐药突变体具有良好结合亲和力的原因。由突变引起的这些氨基酸残基的构象变化总是通过闭合或打开指状结构域和掌状结构域之间的间隙来影响酶-抑制剂复合物三级结构的变化。具有良好结合亲和力的酶-抑制剂复合物通过闭合两个结构域之间的间隙显示出紧密的结合模式，而弱抑制剂则形成开放和松散的复合物。
