Identification of 1H-purine-2,6-dione derivative as a potential SARS-CoV-2 main protease inhibitor: molecular docking, dynamic simulations, and energy calculations

PeerJ

article

Hossam Nada¹  Ahmed Elkamhawy¹  Kyeong Lee¹ 

[1] BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul;Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Badr University in Cairo;Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University

关键词: E-pharmacophore modeling;    Structure-based virtual screening (SBVS);    Molecular dynamics (MD) simulation;    SARS-Cov-2 Mpro;    Free energy calculations;   

DOI  :  10.7717/peerj.14120

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

The rapid spread of the coronavirus since its first appearance in 2019 has taken the world by surprise, challenging the global economy, and putting pressure on healthcare systems across the world. The introduction of preventive vaccines only managed to slow the rising death rates worldwide, illuminating the pressing need for developing effective antiviral therapeutics. The traditional route of drug discovery has been known to require years which the world does not currently have. In silico approaches in drug design have shown promising results over the last decade, helping to decrease the required time for drug development. One of the vital non-structural proteins that are essential to viral replication and transcription is the SARS-CoV-2 main protease (Mpro). Herein, using a test set of recently identified COVID-19 inhibitors, a pharmacophore was developed to screen 20 million drug-like compounds obtained from a freely accessible Zinc database. The generated hits were ranked using a structure based virtual screening technique (SBVS), and the top hits were subjected to in-depth molecular docking studies and MM-GBSA calculations over SARS-COV-2 Mpro. Finally, the most promising hit, compound (1), and the potent standard (III) were subjected to 100 ns molecular dynamics (MD) simulations and in silico ADME study. The result of the MD analysis as well as the in silico pharmacokinetic study reveal compound 1 to be a promising SARS-Cov-2 MPro inhibitor suitable for further development.

【 授权许可】

CC BY