The third variable loop region (V3 loop) on gp120 plays an important role in cellular entry of HIV-1. Its interaction with the cellular CD4 and coreceptors is an important hallmark in facilitating the bridging by gp41 and subsequent fusion of membranes for transfer of viral genetic material. Further, the virus phenotype determines the cell tropism via respective co– receptor binding. Thus, coreceptor binding motif of envelope is considered to be a potent anti-viral drug target for viral entry inhibition. However, its high variability in sequence is the major hurdle for developing inhibitors targeting the region. In this study, we have used an in silico Virtual Screening and “Fragment-based” method to design small molecules based on the gp120 V3 loop interactions with a potent broadly neutralizing human monoclonal antibody, 447-52D. From the in silico analysis a potent scaffold, 1,3,5-triazine was identified for further development. Derivatives of 1,3,5-triazine with specific functional groups were designed and synthesized keeping the interaction with co-receptor intact. Finally, preliminary evaluation of molecules for HIV-1 inhibition on two different virus strains (clade C, clade B) yielded IC50 < 5.0 μM. The approach used to design molecules based on broadly neutralizing antibody, was useful for development of target specific potent antiviral agents to prevent HIV entry. The study reported promising inhibitors that could be further developed and studied.

gp120 上的第三个可变环区（V3 环）在 HIV-1 的细胞进入中起重要作用。它与细胞 CD4 和辅助受体的相互作用是促进 gp41 桥接和随后膜融合以转移病毒遗传物质的重要标志。此外，病毒表型通过各自的共受体结合决定细胞趋向性。因此，包膜的辅助受体结合基序被认为是抑制病毒进入的有效抗病毒药物靶标。然而，其序列的高度可变性是开发针对该区域的抑制剂的主要障碍。在这项研究中，我们使用了一个in silico基于 gp120 V3 环与强效广泛中和人单克隆抗体 447-52D 的相互作用设计小分子的虚拟筛选和“基于片段”的方法。从计算机分析中确定了一种有效的支架，1,3,5-三嗪用于进一步开发。设计并合成了具有特定官能团的 1,3,5-三嗪衍生物，保持与共受体的相互作用完好无损。最后，对两种不同病毒株（进化枝 C、进化枝 B）的 HIV-1 抑制分子的初步评估产生 IC50 < 5.0 μM。用于设计基于广泛中和抗体的分子的方法可用于开发靶向特异性强效抗病毒剂以防止 HIV 进入。该研究报告了可以进一步开发和研究的有前景的抑制剂。