SAR, Molecular Docking and Molecular Dynamic Simulation of Natural Inhibitors against SARS-CoV-2 Mpro Spike Protein

• Published in: Molecules (Basel, Switzerland) Switzerland), 2024-03, Vol.29 (5), p.1144
• Main Authors: Salamat, Aqsa, Kosar, Naveen, Mohyuddin, Ayesha, Imran, Muhammad, Zahid, Muhammad Nauman, Mahmood, Tariq
• Format: Article
• Language: English
• Subjects: Amino acids; Analysis; Animals; Binding sites; Bioavailability; Computer software industry; Coronavirus 3C Proteases; COVID-19; Cricetinae; density functional theory (DFT); Disease transmission; Energy; Flavonoids; Health aspects; Humans; Hydration; Kaempferols; Ligands; Mesocricetus; molecular docking (MD); Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; pharmacokinetics; Phytochemicals; Protease Inhibitors; Proteins; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Simulation methods; Spike Glycoprotein, Coronavirus; structure–activity relationship (SAR); World health
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29051144

The SARS-CoV-2 virus and its mutations have affected human health globally and created significant danger for the health of people all around the world. To cure this virus, the human Angiotensin Converting Enzyme-2 (ACE2) receptor, the SARS-CoV-2 main protease (Mpro), and spike proteins were found to be likely candidates for the synthesis of novel therapeutic drug. In the past, proteins were capable of engaging in interaction with a wide variety of ligands, including both manmade and plant-derived small molecules. L., , , , and were some of the plant species that were studied for their tendency to interact with SARS-CoV-2 main protease (Mpro) in this research project (6LU7). This scenario investigates the geometry, electronic, and thermodynamic properties computationally. Assessing the intermolecular forces of phytochemicals with the targets of the SARS-CoV-2 Mpro spike protein (SP) resulted in the recognition of a compound, kaempferol, as the most potent binding ligand, -7.7 kcal mol . Kaempferol interacted with ASP-187, CYS-145, SER-144, LEU 141, MET-165, and GLU-166 residues. Through additional molecular dynamic simulations, the stability of ligand-protein interactions was assessed for 100 ns. GLU-166 remained intact with 33% contact strength with phenolic OH group. We noted a change in torsional conformation, and the molecular dynamics simulation showed a potential variation in the range from 3.36 to 7.44 against a 45-50-degree angle rotation. SAR, pharmacokinetics, and drug-likeness characteristic investigations showed that kaempferol may be the suitable candidate to serve as a model for designing and developing new anti-COVID-19 medicines.