Jayaswal Amit, Mishra Ankita, Mishra Hirdyesh, Shah Kavita
Bioinformatics Department, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi 221005, India.
Physics Department, MMV, Banaras Hindu University, Varanasi 221005, India.
Bioinformation. 2014 Apr 23;10(4):227-32. doi: 10.6026/97320630010227. eCollection 2014.
A fundamental issue related to therapy of HIV-1 infection is the emergence of viral mutations which severely limits the long term efficiency of the HIV-protease (HIV-PR) inhibitors. Development of new drugs is therefore continuously needed. Chemoinformatics enables to design and discover novel molecules analogous to established drugs using computational tools and databases. Saquinavir, an anti-HIV Protease drug is administered for HIV therapy. In this work chemoinformatics tools were used to design structural analogs of Saquinavir as ligand and molecular dockings at AutoDock were performed to identify potential HIV-PR inhibitors. The analogs S1 and S2 when docked with HIV-PR had binding energies of -4.08 and -3.07 kcal/mol respectively which were similar to that for Saquinavir. The molecular docking studies revealed that the changes at N2 of Saquinavir to obtain newly designed analogs S1 (having N2 benzoyl group at N1) and S2 (having 3-oxo-3phenyl propanyl group at N2) were able to dock with HIV-PR with similar affinity as that of Saquinavir. Docking studies and computationally derived pharmacodynamic and pharmacokinetic properties׳ comparisons at ACD/I-lab establish that analog S2 has more potential to evade the problem of drug resistance mutation against HIV-1 PR subtype-A. S2 can be further developed and tested clinically as a real alternative drug for HIV-1 PR across the clades in future.
与HIV-1感染治疗相关的一个基本问题是病毒突变的出现，这严重限制了HIV蛋白酶（HIV-PR）抑制剂的长期疗效。因此，持续需要开发新药。化学信息学能够利用计算工具和数据库设计并发现与现有药物类似的新型分子。沙奎那韦是一种用于HIV治疗的抗HIV蛋白酶药物。在这项工作中，使用化学信息学工具设计沙奎那韦的结构类似物作为配体，并在AutoDock上进行分子对接以识别潜在的HIV-PR抑制剂。类似物S1和S2与HIV-PR对接时的结合能分别为-4.08和-3.07 kcal/mol，与沙奎那韦的结合能相似。分子对接研究表明，沙奎那韦N2处的变化产生了新设计的类似物S1（N1处有N2苯甲酰基）和S2（N2处有3-氧代-3-苯基丙酰基），它们能够以与沙奎那韦相似的亲和力与HIV-PR对接。在ACD/I-lab进行的对接研究以及计算得出的药效学和药代动力学性质比较表明，类似物S2更有潜力规避针对HIV-1 PR A亚型的耐药性突变问题。未来，S2可以进一步开发并作为针对HIV-1 PR跨进化枝的真正替代药物进行临床测试。
