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设计、合成、对接和非核苷 SARS-CoV-2 RdRp 抑制剂的生化特性分析。

Design, synthesis, docking, and biochemical characterization of non-nucleoside SARS-CoV-2 RdRp inhibitors.

机构信息

Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.

Analytical Chemistry, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.

出版信息

Bioorg Med Chem. 2023 Feb 15;80:117179. doi: 10.1016/j.bmc.2023.117179. Epub 2023 Jan 21.

DOI:10.1016/j.bmc.2023.117179
PMID:36716583
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9862713/
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic. The identification of effective antiviral drugs remains an urgent medical need. In this context, here we report 17 new 1,4-benzopyrone derivatives, which have been designed, synthesized, and characterized for their ability to block the RNA-dependent RNA polymerase (RdRp) enzyme, a promising target for antiviral drug discovery. This compound series represents a good starting point for developing non-nucleoside inhibitors of RdRp. Compounds 4, 5, and 8 were the most promising drug-like candidates with good potency in inhibiting RdRp, improved in vitro pharmacokinetics compared to the initial hits, and no cytotoxicity effects on normal cell (HEK-293). Compound 8 (ARN25592) stands out as the most promising inhibitor. Our results indicate that this new chemical class of 1,4-benzopyrone derivatives deserves further exploration towards novel and potent antiviral drugs for the treatment of SARS-CoV-2 and potentially other viruses.

摘要

严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）已造成全球大流行。寻找有效的抗病毒药物仍然是当务之急。在此背景下，我们报告了 17 种新的 1,4-苯并吡喃酮衍生物，这些化合物经过设计、合成和表征，具有抑制 RNA 依赖性 RNA 聚合酶（RdRp）酶的能力，RdRp 酶是抗病毒药物发现的一个有前途的靶点。该化合物系列为开发非核苷类 RdRp 抑制剂提供了一个良好的起点。化合物 4、5 和 8 是最有前途的类药性候选物，对 RdRp 的抑制活性高，与初始命中物相比，体外药代动力学得到改善，对正常细胞（HEK-293）无细胞毒性作用。化合物 8（ARN25592）是最有前途的抑制剂。我们的研究结果表明，这种新的 1,4-苯并吡喃酮类衍生物值得进一步探索，以开发新型有效的抗病毒药物，用于治疗 SARS-CoV-2 并可能治疗其他病毒。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/a9f9d8dd89ad/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/e2ccb60dbfca/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/ba4ff7c94239/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/aac6ee9330c8/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/018b46bb986c/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/5a9952443e92/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/d2a9a0be8542/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/6b9c35b36965/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/8b6ee8420406/gr9_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/52847701d71f/gr10_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/9eba1636172b/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/a9f9d8dd89ad/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/e2ccb60dbfca/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/ba4ff7c94239/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/aac6ee9330c8/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/018b46bb986c/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/5a9952443e92/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/d2a9a0be8542/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/6b9c35b36965/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/8b6ee8420406/gr9_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/52847701d71f/gr10_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/9eba1636172b/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3713/9862713/a9f9d8dd89ad/gr4_lrg.jpg

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