Dual inhibitor design for HIV-1 reverse transcriptase and integrase enzymes: a molecular docking study

HIV-1, a member of Retroviruses’ Lentivirus family, is the causative agent of AIDS. The virus is common throughout the world and leaves the body vulnerable to infections by suppressing the human immune system. Reverse transcriptase and integrase are two of three HIV-1 essential enzymes which perform important virus life cycle functions. In recent years, researchers started to design new inhibitors which could inhibit multiple targets for treatment of AIDS. In respect to this, RT and IN are two enzymes suitable for the development of dual inhibitors. To realize this aim, here we have designed new inhibitors by using approved reverse transcriptase and integrase inhibitors as drug design templates. Totally 426 ligands, which are filtered from 858 ligands by druggability properties were docked to crystal structure of reverse transcriptase and since there was no full-length structure of HIV-1 IN, same ligands were docked to Prototype Foamy Virus integrase structure. From the docking results, B099 was determined to be the best binding ligand to RT enzyme with a binding free energy of −12.63 kcal/mole and B249 was the best ligand for IN enzyme with a score of −19.83 kcal/mole. These binding scores demonstrate that these ligands are more active than Raltegravir for integrase and Rilpivirine for reverse transcriptase which are also used for docking method validation. B205, B214, B233, B242, B246, B249, B253 and B254 are the some of ligands found to have good binding scores for both enzymes and could be considered as new inhibitor candidates as dual inhibitors. Communicated by Ramaswamy H. Sarma

人类免疫缺陷病毒1型（HIV-1）隶属于逆转录病毒科慢病毒属，是艾滋病（AIDS）的致病病原体。该病毒在全球范围内广泛流行，可通过抑制人体免疫系统使机体极易遭受各类感染侵袭。逆转录酶（reverse transcriptase，下文简称RT）与整合酶（integrase，下文简称IN）是HIV-1三种必需酶中的两种，二者在病毒生命周期中发挥关键功能。近年来，研究人员开始设计可靶向多靶点的新型抑制剂用于艾滋病治疗。鉴于此，RT与IN成为开发双重抑制剂的理想靶点。为实现这一目标，本研究以已获批的逆转录酶抑制剂与整合酶抑制剂作为药物设计模板，构建了新型抑制剂分子。本研究从858个配体（ligand）中基于成药性筛选出426个配体，将其与RT的晶体结构进行分子对接；由于目前尚无全长的HIV-1 IN晶体结构，因此将上述配体与原型泡沫病毒（Prototype Foamy Virus）整合酶的晶体结构进行对接。分子对接结果显示，B099是与RT结合效果最佳的配体，其结合自由能为-12.63 kcal/mol；B249则是与IN结合效果最佳的配体，结合得分为-19.83 kcal/mol。上述结合得分表明，相较于用于验证分子对接方法的阳性对照药物——整合酶抑制剂拉替拉韦（Raltegravir）与逆转录酶抑制剂利匹韦林（Rilpivirine），本研究筛选出的配体展现出更优的结合活性。其中B205、B214、B233、B242、B246、B249、B253及B254等配体对两种酶均表现出优异的结合得分，可作为潜在的双重抑制剂候选药物。本稿件由拉马萨米·H·萨尔马（Ramaswamy H. Sarma）提交。