College of Medicine and Public Health, Flinders University, Bedford Park 5046, Australia.
Vaxine Pty Ltd., 11 Walkley Avenue, Warradale 5046, Australia.
Int J Mol Sci. 2023 Feb 20;24(4):4192. doi: 10.3390/ijms24044192.
Drugs against novel targets are needed to treat COVID-19 patients, especially as SARS-CoV-2 is capable of rapid mutation. Structure-based de novo drug design and repurposing of drugs and natural products is a rational approach to discovering potentially effective therapies. These in silico simulations can quickly identify existing drugs with known safety profiles that can be repurposed for COVID-19 treatment. Here, we employ the newly identified spike protein free fatty acid binding pocket structure to identify repurposing candidates as potential SARS-CoV-2 therapies. Using a validated docking and molecular dynamics protocol effective at identifying repurposing candidates inhibiting other SARS-CoV-2 molecular targets, this study provides novel insights into the SARS-CoV-2 spike protein and its potential regulation by endogenous hormones and drugs. Some of the predicted repurposing candidates have already been demonstrated experimentally to inhibit SARS-CoV-2 activity, but most of the candidate drugs have yet to be tested for activity against the virus. We also elucidated a rationale for the effects of steroid and sex hormones and some vitamins on SARS-CoV-2 infection and COVID-19 recovery.
需要针对新型靶点的药物来治疗 COVID-19 患者，特别是因为 SARS-CoV-2 能够快速突变。基于结构的从头药物设计和药物及天然产物的再利用是发现潜在有效疗法的合理方法。这些计算机模拟可以快速识别具有已知安全性的现有药物，这些药物可被重新用于 COVID-19 的治疗。在这里，我们利用新鉴定的刺突蛋白游离脂肪酸结合口袋结构来鉴定重新利用的候选药物作为潜在的 SARS-CoV-2 治疗方法。本研究使用经过验证的对接和分子动力学方案，有效地鉴定了重新利用候选药物抑制其他 SARS-CoV-2 分子靶点，为 SARS-CoV-2 刺突蛋白及其受内源性激素和药物调节的潜在机制提供了新的见解。一些预测的再利用候选药物已经在实验中被证明可以抑制 SARS-CoV-2 的活性，但大多数候选药物尚未针对该病毒进行活性测试。我们还阐明了类固醇和性激素以及一些维生素对 SARS-CoV-2 感染和 COVID-19 恢复的影响的基本原理。
