Keli Zong, Chaochun Wei, Wei Li, Jiajun Ruan, Susu Zhang, Jingjing Li, Xiaojing Liu, Xu Zhao, Ruiyuan Cao, Hong Yan, Xingzhou Li
{"title":"通过分子对接、体外试验、分子动力学模拟和 DFT 分析鉴定新型 SARS-CoV-2 3CLpro 抑制剂。","authors":"Keli Zong, Chaochun Wei, Wei Li, Jiajun Ruan, Susu Zhang, Jingjing Li, Xiaojing Liu, Xu Zhao, Ruiyuan Cao, Hong Yan, Xingzhou Li","doi":"10.3389/fphar.2024.1494953","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>SARS-CoV-2 pandemic has presented a significant threat to global health and the economy, necessitating urgent efforts to develop effective antiviral drugs. The main protease (3CLpro) of SARS-CoV-2 is a critical target for antiviral therapy due to its essential role in viral replication.</p><p><strong>Methods: </strong>In order to find new structural types of 3CLpro inhibitors to facilitate the solution to the problem of new virus resistance. Six potential pharmacologically bioactive compounds were identified by utilizing structure-based virtual screening and <i>in vitro</i> assays from the Topscience database containing 10 million compounds.</p><p><strong>Results and discussion: </strong>Among these, compounds 34 and 36 exhibited potent inhibitory activity with IC<sub>50</sub> values of 6.12 ± 0.42 μM and 4.47 ± 0.39 μM, respectively. To elucidate their binding mechanisms with 3CLpro, all-atom molecular dynamics (MD) simulations were conducted. Principal component analysis (PCA), free energy landscapes (FEL) and dynamic cross-correlation maps (DCCM) revealed that the binding of compounds 34 and 36 to 3CLpro significantly enhanced the structural stability of 3CLpro, reducing conformational flexibility and internal motions. The results of protein-ligand interaction showed that compounds 34 and 36 formed strong and stable interactions to key residues at active site of 3CLpro with different binding modes from S-217622. And HOMO-LUMO gap and molecular electrostatic potential distribution revealed the quantum chemical properties of compounds 34 and 36. These findings suggested that compounds 34 and 36 can be as novel SARS-CoV-2 3CLpro inhibitors and promising lead-like drug candidates for developing COVID-19 treatments.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1494953"},"PeriodicalIF":4.4000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557435/pdf/","citationCount":"0","resultStr":"{\"title\":\"Identification of novel SARS-CoV-2 3CLpro inhibitors by molecular docking, <i>in vitro</i> assays, molecular dynamics simulations and DFT analyses.\",\"authors\":\"Keli Zong, Chaochun Wei, Wei Li, Jiajun Ruan, Susu Zhang, Jingjing Li, Xiaojing Liu, Xu Zhao, Ruiyuan Cao, Hong Yan, Xingzhou Li\",\"doi\":\"10.3389/fphar.2024.1494953\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>SARS-CoV-2 pandemic has presented a significant threat to global health and the economy, necessitating urgent efforts to develop effective antiviral drugs. The main protease (3CLpro) of SARS-CoV-2 is a critical target for antiviral therapy due to its essential role in viral replication.</p><p><strong>Methods: </strong>In order to find new structural types of 3CLpro inhibitors to facilitate the solution to the problem of new virus resistance. Six potential pharmacologically bioactive compounds were identified by utilizing structure-based virtual screening and <i>in vitro</i> assays from the Topscience database containing 10 million compounds.</p><p><strong>Results and discussion: </strong>Among these, compounds 34 and 36 exhibited potent inhibitory activity with IC<sub>50</sub> values of 6.12 ± 0.42 μM and 4.47 ± 0.39 μM, respectively. To elucidate their binding mechanisms with 3CLpro, all-atom molecular dynamics (MD) simulations were conducted. Principal component analysis (PCA), free energy landscapes (FEL) and dynamic cross-correlation maps (DCCM) revealed that the binding of compounds 34 and 36 to 3CLpro significantly enhanced the structural stability of 3CLpro, reducing conformational flexibility and internal motions. The results of protein-ligand interaction showed that compounds 34 and 36 formed strong and stable interactions to key residues at active site of 3CLpro with different binding modes from S-217622. And HOMO-LUMO gap and molecular electrostatic potential distribution revealed the quantum chemical properties of compounds 34 and 36. These findings suggested that compounds 34 and 36 can be as novel SARS-CoV-2 3CLpro inhibitors and promising lead-like drug candidates for developing COVID-19 treatments.</p>\",\"PeriodicalId\":12491,\"journal\":{\"name\":\"Frontiers in Pharmacology\",\"volume\":\"15 \",\"pages\":\"1494953\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-10-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557435/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3389/fphar.2024.1494953\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fphar.2024.1494953","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Identification of novel SARS-CoV-2 3CLpro inhibitors by molecular docking, in vitro assays, molecular dynamics simulations and DFT analyses.
Introduction: SARS-CoV-2 pandemic has presented a significant threat to global health and the economy, necessitating urgent efforts to develop effective antiviral drugs. The main protease (3CLpro) of SARS-CoV-2 is a critical target for antiviral therapy due to its essential role in viral replication.
Methods: In order to find new structural types of 3CLpro inhibitors to facilitate the solution to the problem of new virus resistance. Six potential pharmacologically bioactive compounds were identified by utilizing structure-based virtual screening and in vitro assays from the Topscience database containing 10 million compounds.
Results and discussion: Among these, compounds 34 and 36 exhibited potent inhibitory activity with IC50 values of 6.12 ± 0.42 μM and 4.47 ± 0.39 μM, respectively. To elucidate their binding mechanisms with 3CLpro, all-atom molecular dynamics (MD) simulations were conducted. Principal component analysis (PCA), free energy landscapes (FEL) and dynamic cross-correlation maps (DCCM) revealed that the binding of compounds 34 and 36 to 3CLpro significantly enhanced the structural stability of 3CLpro, reducing conformational flexibility and internal motions. The results of protein-ligand interaction showed that compounds 34 and 36 formed strong and stable interactions to key residues at active site of 3CLpro with different binding modes from S-217622. And HOMO-LUMO gap and molecular electrostatic potential distribution revealed the quantum chemical properties of compounds 34 and 36. These findings suggested that compounds 34 and 36 can be as novel SARS-CoV-2 3CLpro inhibitors and promising lead-like drug candidates for developing COVID-19 treatments.
期刊介绍:
Frontiers in Pharmacology is a leading journal in its field, publishing rigorously peer-reviewed research across disciplines, including basic and clinical pharmacology, medicinal chemistry, pharmacy and toxicology. Field Chief Editor Heike Wulff at UC Davis is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.