Kapoor Shreya, Singh Anurag, Gupta Vandana
Department of Microbiology, Ram Lal Anand College, University of Delhi, Benito Juarez Road, New Delhi, 110021, India.
Delhi Technological University, New Delhi, India.
Phys Chem Earth (2002). 2023 Feb;129:103350. doi: 10.1016/j.pce.2022.103350. Epub 2022 Dec 15.
With few available effective interventions, emergence of novel mutants responding poorly to existing vaccines and ever swelling newer waves of infection, SARS-CoV-2 is posing difficult challenges to mankind. This mandates development of newer and effective therapeutics to prevent loss of life and contain the spread of this deadly virus. Nsp12 or RNA-dependent RNA polymerase (RdRp) is a suitable druggable target as it plays a central role in viral replication.
Catalytically important conserved amino acid residues of RdRp were delineated through a comprehensive literature search and multiple sequence alignments. PDB ID 7BV2 was used to create binding pockets using SeeSAR and to generate docked poses of the FDA approved drugs on the receptor and estimating their binding affinity and other properties.
approach used in this study assisted in prediction of several potential RdRp inhibitors; and re-validation of the already reported ones. Five molecules namely Inosine, Ribavirin, 2-Deoxy-2-Fluoro-D-glucose, Guaifenesin, and Lamivudine were shortlisted which exhibited reasonable binding affinities, with neither torsional nor intermolecular or intramolecular clashes.
This study aimed to widen the prospect of interventions against the SARS-CoV-2 RdRp. Our results also re-validate already reported molecules like 2-Deoxy-D-glucose as a similar molecule 2-deoxy-2-fluoro-D-glucose is picked up in this study. Additionally, ribavirin and lamivudine, already known antivirals with polymerase inhibition activity are also picked up as the top leads. Selected potent inhibitors of RdRp hold promise to cater for any future coronavirus-outbreak subject to and validations.
由于可用的有效干预措施很少，出现了对现有疫苗反应不佳的新型突变体，且感染新一波浪潮不断涌现，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）给人类带来了严峻挑战。这就要求开发更新、更有效的治疗方法，以防止生命损失并遏制这种致命病毒的传播。非结构蛋白12（Nsp12）或RNA依赖性RNA聚合酶（RdRp）是一个合适的可成药靶点，因为它在病毒复制中起核心作用。
通过全面的文献检索和多序列比对，确定了RdRp的催化重要保守氨基酸残基。使用SeeSAR以蛋白质数据银行（PDB）编号7BV2创建结合口袋，并生成美国食品药品监督管理局（FDA）批准药物在该受体上的对接构象，同时估计它们的结合亲和力和其他性质。
本研究中使用的方法有助于预测几种潜在的RdRp抑制剂，并对已报道的抑制剂进行重新验证。筛选出了肌苷、利巴韦林、2-脱氧-2-氟-D-葡萄糖、愈创甘油醚和拉米夫定这五种分子，它们表现出合理的结合亲和力，既没有扭转冲突，也没有分子间或分子内冲突。
本研究旨在拓宽针对SARS-CoV-2 RdRp的干预前景。我们的结果还重新验证了已报道的分子，如2-脱氧-D-葡萄糖，因为本研究中挑选出了类似分子2-脱氧-2-氟-D-葡萄糖。此外，已知具有聚合酶抑制活性的抗病毒药物利巴韦林和拉米夫定也被选为主要先导药物。选定的强效RdRp抑制剂有望应对未来任何冠状病毒爆发，但需经过进一步验证。
