Cullen Matthew D, Ho William C, Bauman Joseph D, Das Kalyan, Arnold Eddy, Hartman Tracy L, Watson Karen M, Buckheit Robert W, Pannecouque Christophe, De Clercq Erik, Cushman Mark
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 2009 Oct 22;52(20):6467-73. doi: 10.1021/jm901167t.
Two crystal structures have been solved for separate complexes of alkenyldiarylmethane (ADAM) nonnucleoside reverse transcriptase inhibitors (NNRTI) 3 and 4 with HIV-1 reverse transcriptase (RT). The structures reveal inhibitor binding is exclusively hydrophobic in nature and the shape of the inhibitor-bound NNRTI binding pocket is unique among other reported inhibitor-RT crystal structures. Primarily, ADAMs 3 and 4 protrude from a large gap in the back side of the binding pocket, placing portions of the inhibitors unusually close to the polymerase active site and allowing 3 to form a weak hydrogen bond with Lys223. The lack of additional stabilizing interactions, beyond the observed hydrophobic surface contacts, between 4 and RT is quite perplexing given the extreme potency of the compound (IC(50) </= 1 nM). ADAM 4 was designed to be hydrolytically stable in blood plasma, and an investigation of its hydrolysis in rat plasma demonstrated it has a significantly prolonged half-life in comparison to ADAM lead compounds 1 and 2.
已解析了链烯基二芳基甲烷（ADAM）非核苷类逆转录酶抑制剂（NNRTI）3和4与HIV-1逆转录酶（RT）的不同复合物的两种晶体结构。这些结构表明抑制剂结合本质上完全是疏水的，并且在其他已报道的抑制剂-RT晶体结构中，与抑制剂结合的NNRTI结合口袋的形状是独特的。主要地，ADAMs 3和4从结合口袋背面的一个大间隙中突出，使抑制剂的部分异常靠近聚合酶活性位点，并使3与Lys223形成一个弱氢键。鉴于该化合物的极高效力（IC(50)≤1 nM），4与RT之间除了观察到的疏水表面接触外缺乏额外的稳定相互作用，这相当令人困惑。ADAM 4设计为在血浆中具有水解稳定性，对其在大鼠血浆中的水解研究表明，与ADAM先导化合物1和2相比，它具有显著延长的半衰期。
