使用多步骤计算工作流程快速优化人类免疫缺陷病毒 1 型衣壳抑制剂的代谢稳定性。
Rapid Optimization of the Metabolic Stability of a Human Immunodeficiency Virus Type-1 Capsid Inhibitor Using a Multistep Computational Workflow.
机构信息
Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Rooms 10307, 10309, and 10315, 245 North 15th Street, Philadelphia, Pennsylvania 19102, United States.
The Wistar Cancer Center Molecular Screening, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
出版信息
J Med Chem. 2021 Apr 8;64(7):3747-3766. doi: 10.1021/acs.jmedchem.0c01810. Epub 2021 Mar 22.
Abstract
Poor metabolic stability of the human immunodeficiency virus type-1 (HIV-1) capsid (CA) inhibitor is a major concern in its development toward clinical use. To improve on the metabolic stability, we employed a novel multistep computationally driven workflow, which facilitated the rapid design of improved analogs in an efficient manner. Using this workflow, we designed three compounds that interact specifically with the CA interprotomer pocket, inhibit HIV-1 infection, and demonstrate enantiomeric preference. Moreover, using this workflow, we were able to increase the metabolic stability 204-fold in comparison to in only three analog steps. These results demonstrate our ability to rapidly design CA compounds using a novel computational workflow that has improved metabolic stability over the parental compound. This workflow can be further applied to the redesign of and other promising inhibitors with a stability shortfall.
摘要
人类免疫缺陷病毒 1 型（HIV-1）衣壳（CA）抑制剂的代谢稳定性差，是其向临床应用发展的主要关注点。为了提高代谢稳定性，我们采用了一种新的多步骤计算驱动的工作流程，该流程以高效的方式促进了改进型类似物的快速设计。使用此工作流程，我们设计了三种与 CA 互变异构口袋特异性相互作用、抑制 HIV-1 感染并表现出对映体选择性的化合物。此外，使用此工作流程，我们能够将代谢稳定性与相比提高 204 倍，仅通过三个类似物步骤。这些结果表明，我们能够使用新的计算工作流程快速设计 CA 化合物，该工作流程在母体化合物的基础上提高了代谢稳定性。该工作流程可以进一步应用于其他具有稳定性缺陷的 和其他有前途的抑制剂的重新设计。
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