Computational Toxicology Facility, CSIR- Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
Computational Toxicology Facility, CSIR- Indian Institute of Toxicology Research, Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.
Comput Biol Med. 2021 Mar;130:104222. doi: 10.1016/j.compbiomed.2021.104222. Epub 2021 Jan 20.
COVID-19 outbreak poses a severe health emergency to the global community. Due to availability of limited data, the selection of an effective treatment is a challenge. Hydroxychloroquine (HCQ), a chloroquine (CQ) derivative administered for malaria and autoimmune diseases, has been shown to be effective against both Severe Acute Respiratory Syndrome (SARS-CoV-1) and SARS-CoV-2. Apart from the known adverse effects of these drugs, recently the use of CQ and HCQ as a potential treatment for COVID-19 is under flux globally. In this study, we focused on identifying a more potent analogue of HCQ and CQ against the spike protein of SAR-CoV-2 that can act as an effective antiviral agent for COVID-19 treatment. Systematic pharmacokinetics, drug-likeness, basicity predictions, virtual screening and molecular dynamics analysis (200 ns) were carried out to predict the inhibition potential of the analogous compounds on the spike protein. This work identifies the six potential analogues, out of which two compounds, namely 1-[1-(6-Chloroquinolin-4-yl) piperidin-4-yl]piperidin-3-ol and (1R,2R)-2-N-(7-Chloroquinolin-4-yl)cyclohexane-1,2-diamine interact with the active site of the spike protein similar to HCQ and CQ respectively with augmented safety profile.
COVID-19 疫情对全球社会构成了严重的健康紧急情况。由于数据有限，选择有效的治疗方法是一个挑战。羟氯喹（HCQ），一种氯喹（CQ）衍生物，用于治疗疟疾和自身免疫性疾病，已被证明对严重急性呼吸综合征（SARS-CoV-1）和 SARS-CoV-2 均有效。除了这些药物已知的不良反应外，最近全球范围内正在使用 CQ 和 HCQ 作为 COVID-19 的潜在治疗方法。在这项研究中，我们专注于鉴定一种针对 SAR-CoV-2 刺突蛋白的更有效的 HCQ 和 CQ 类似物，该类似物可以作为 COVID-19 治疗的有效抗病毒药物。进行了系统药代动力学、药物相似性、碱性预测、虚拟筛选和分子动力学分析（200ns），以预测类似物对刺突蛋白的抑制潜力。这项工作确定了六个潜在的类似物，其中两种化合物，即 1-[1-(6-氯喹啉-4-基)哌啶-4-基]哌啶-3-醇和(1R,2R)-2-N-(7-氯喹啉-4-基)环己烷-1,2-二胺，与 HCQ 和 CQ 分别与刺突蛋白的活性位点相互作用，安全性更高。
