PDF(Pubmed)
Abstract：
The prevalence of HIV-1 infection continues to pose a significant global public health issue, highlighting the need for antiretroviral drugs that target viral proteins to reduce viral replication. One such target is HIV-1 protease (PR), responsible for cleaving viral polyproteins, leading to the maturation of viral proteins. While darunavir (DRV) is a potent HIV-1 PR inhibitor, drug resistance can arise due to mutations in HIV-1 PR. To address this issue, we developed a novel approach using the fragment molecular orbital (FMO) method and structure-based drug design to create DRV analogs. Using combinatorial programming, we generated novel analogs freely accessible via an on-the-cloud mode implemented in Google Colab, Combined Analog generator Tool (CAT). The designed analogs underwent cascade screening through molecular docking with HIV-1 PR wild-type and major mutations at the active site. Molecular dynamics (MD) simulations confirmed the assess ligand binding and susceptibility of screened designed analogs. Our findings indicate that the three designed analogs guided by FMO, 19-0-14-3, 19-8-10-0, and 19-8-14-3, are superior to DRV and have the potential to serve as efficient PR inhibitors. These findings demonstrate the effectiveness of our approach and its potential to be used in further studies for developing new antiretroviral drugs.
摘要：
艾滋病毒-1感染的流行继续构成重大的全球公共卫生问题。强调需要针对病毒蛋白的抗逆转录病毒药物来减少病毒复制。一个这样的靶标是HIV-1蛋白酶（PR），负责切割病毒多蛋白，导致病毒蛋白的成熟。虽然达鲁那韦（DRV）是一种有效的HIV-1PR抑制剂，由于HIV-1PR的突变，可能会产生耐药性。为了解决这个问题，我们开发了一种使用片段分子轨道（FMO）方法和基于结构的药物设计来创建DRV类似物的新方法。使用组合编程，我们通过GoogleColab中实现的云模式生成了可自由访问的新颖类似物，组合模拟生成器工具(CAT)。设计的类似物通过与HIV-1PR野生型和活性位点的主要突变的分子对接进行级联筛选。分子动力学(MD)模拟证实了所筛选的设计类似物的评估配体结合和敏感性。我们的研究结果表明，在FMO指导下设计的三种类似物，19-0-14-3、19-8-10-0和19-8-14-3优于DRV并且具有作为有效PR抑制剂的潜力。这些发现证明了我们的方法的有效性及其在进一步研究中用于开发新的抗逆转录病毒药物的潜力。
