Virtual screening, molecular dynamics and structure-activity relationship studies to identify potent approved drugs for Covid-19 treatment.
Md Mahbubur RahmanTiton SahaKazi Jahidul IslamRasel Hosen SumanSourav BiswasEmon Uddin RahatMd Rubel HossenRajib IslamMd Nayeem HossainAbdulla Al MamunMaksud KhanMd Ackas AliMohammad Abdul HalimPublished in: Journal of biomolecular structure & dynamics (2020)
Computer-aided drug screening by molecular docking, molecular dynamics (MD) and structural-activity relationship (SAR) can offer an efficient approach to identify promising drug repurposing candidates for COVID-19 treatment. In this study, computational screening is performed by molecular docking of 1615 Food and Drug Administration (FDA) approved drugs against the main protease (Mpro) of SARS-CoV-2. Several promising approved drugs, including Simeprevir, Ergotamine, Bromocriptine and Tadalafil, stand out as the best candidates based on their binding energy, fitting score and noncovalent interactions at the binding sites of the receptor. All selected drugs interact with the key active site residues, including His41 and Cys145. Various noncovalent interactions including hydrogen bonding, hydrophobic interactions, pi-sulfur and pi-pi interactions appear to be dominant in drug-Mpro complexes. MD simulations are applied for the most promising drugs. Structural stability and compactness are observed for the drug-Mpro complexes. The protein shows low flexibility in both apo and holo form during MD simulations. The MM/PBSA binding free energies are also measured for the selected drugs. For pattern recognition, structural similarity and binding energy prediction, multiple linear regression (MLR) models are used for the quantitative structural-activity relationship. The binding energy predicted by MLR model shows an 82% accuracy with the binding energy determined by molecular docking. Our details results can facilitate rational drug design targeting the SARS-CoV-2 main protease.Communicated by Ramaswamy H. Sarma.
Keyphrases
- molecular dynamics
- molecular docking
- sars cov
- density functional theory
- drug administration
- molecular dynamics simulations
- drug induced
- binding protein
- coronavirus disease
- dna binding
- respiratory syndrome coronavirus
- adverse drug
- emergency department
- small molecule
- climate change
- case control
- amino acid
- cancer therapy
- benign prostatic hyperplasia
- anti inflammatory