ABSTRACT

HIV-1 gp120 provides a multistage viral entry process through the conserved CD4 binding site. Hunting of potential blockers can diminish the interaction of gp120 with the CD4 host receptor leading to the suppression of HIV-1 infection. Structure-based pharmacophore virtual screening followed by binding free energy calculation, molecular dynamics (MD) simulation and density functional theory (DFT) calculation is applied to discriminate the potential blockers from six small molecule databases. Five compounds from six databases exhibited vital interactions with key residues ASP368, GLU370, ASN425, MET426, TRP427 and GLY473 of gp120, involved in the binding with CD4, host receptor. Most importantly, compound NCI-254200 displayed strong communication with key residues of wild type and drug resistance single mutant gp120 (M426L and W427V) even in the dynamic condition, evidenced from MD simulation. This investigation provided a potential compound NCI-254200 which may show inhibitory activity against HIV-1 gp120 variant interactions with CD4 host cell receptors.

摘要

HIV-1 gp120通过保守的CD4结合位点提供多阶段病毒进入过程。寻找潜在的阻滞剂可以减少gp120与CD4宿主受体的相互作用，从而抑制HIV-1感染。基于结构的药效团虚拟筛选，然后进行结合自由能计算，分子动力学（MD）模拟和密度泛函理论（DFT）计算，以从六个小分子数据库中识别出潜在的阻滞剂。来自六个数据库的五个化合物表现出与gp120的关键残基ASP368，GLU370，ASN425，MET426，TRP427和GLY473的重要相互作用，参与与CD4，宿主受体的结合。最重要的是，化合物NCI-254200甚至在动态条件下也显示出与野生型关键残基和耐药性单个突变体gp120（M426L和W427V）的强连通性，这是通过MD模拟证明的。这项研究提供了一种潜在的化合物NCI-254200，该化合物可能显示出对HIV-1 gp120变异体与CD4宿主细胞受体相互作用的抑制活性。