Molecular optimization, docking, and dynamic simulation profiling of selective aromatic phytochemical ligands in blocking the SARS-CoV-2 S protein attachment to ACE2 receptor: an in silico approach of targeted drug designing

Abstract

Objectives: The comprehensive in silico study aims to figure out the most effective aromatic phytochemical ligands among a number from a library, considering their pharmacokinetic efficacies in blocking “angiotensin-converting enzyme 2 (ACE2) receptor–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein” complex formation as part of a target-specific drug designing. Materials and Methods: A library of 57 aromatic pharmacophore phytochemical ligands was prepared from where the top five ligands depending on Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) and quantitative structure-activity relationship (QSAR)-based pharmacokinetic properties were considered. The selected ligands were optimized for commencing molecular docking and dynamic simulation as a complex with the ACE2 receptor to compare their blocking efficacy with the control drug. The ligand–receptor complexes’ accuracy in preventing the Spike (S) protein of SARS-CoV-2 penetration inside the host cells has been analyzed through hydrogen–hydrophobic bond interactions, principal component analysis (PCA), root mean square deviation (RMSD), root mean square fluctuation (RMSF), and B-Factor. Advanced in silico programming language and bioanalytical software were used for high throughput and authentic results. Results: ADMET and QSAR revealed Rhamnetin, Lactupicrin, Rhinacanthin D, Flemiflavanone D, and Exiguaflavanone A as the ligands of our interest to be compared with the control Cassiarin D. According to the molecular docking binding affinity to block ACE2 receptor, the efficiency mountings were Rhinacanthin D > Flemiflavanone D > Lactupicrin > Exiguaflavanone A > Rhamnetin. The binding affinity of the Cassiarin D–ACE2 complex was (−10.2 KJ/mol) found inferior to the Rhinacanthin D–ACE2 complex (−10.8 KJ/mol), referring to Rhinacanthin D as a more stable candidate to use as drugs. The RMSD values of protein–ligand complexes evaluated according to their structural conformation and stable binding pose ranged between 0.1~2.1 Å. The B-factor showed that very few loops were present in the protein structure. The RMSF peak fluctuation regions ranged 5–250, predicting efficient ligand–receptor interactions. Conclusion: The experiment sequentially measures all the parameters required in referring to any pharmacophore as a drug, considering which all aromatic components analyzed in the study can strongly be predicted as target-specific medication against the novel coronavirus 2019 infection.

Analysis of SYK Gene as a Prognostic Biomarker and Suggested Potential Bioactive Phytochemicals as an Alternative Therapeutic Option for Colorectal Cancer: An In-Silico Pharmaco-Informatics Investigation

“…Molecular docking is the process that estimates how two or more molecules bind together with the best structural confirmation and the lowest binding energy. The more significant and efficient drug candidates were selected based on the scoring value of molecular docking using the PyRx virtual screening tool [Version: 0.8] [ 44 , 45 ]. The docking operation for the five phytochemicals and control molecules with receptor SYK kinase found that the docking score of the control was −6.5 Kcal/mol.…”

“…Unnecessary things were eliminated, such as the water molecules, metal ions, ligands, heteroatoms, and unwanted side chains. Indispensable hydrogen bonds were also added to the macromolecules for more precise docking, and the total operation was conducted by the “UCSF Chimera package tool (Version-1.14)”, here must followed the “Gasteiger’s method” [ 44 ]. The prepared protein structures were saved in PDB format and conserved for further analysis [ 45 ].…”

Active site-specific quantum tunneling of hACE2 receptor to assess its complexing poses with selective bioactive compounds in co-suppressing SARS-CoV-2 influx and subsequent cardiac injury

“…For the initial visualization and qualitative receptor–ligand interactions analysis, Discovery Studio Visualizer (version 3.0) and PyMOL (version 2.4.1) were used sequentially, and the output files were saved as PDB files. Afterward, the quantitative hydrophobic interactions and the number of hydrogen bond formations between each of the protein–ligand complexes were analyzed using LigPlot+ (version 2.2) [ 32 ] before conducting the molecular dynamic simulation.…”

Quantitative Analysis of the Steroidal Calcitriol-Mediated Regulation of the Serological Components Responsible for IDA and TSH Disorders in Reproductive and Nonproductive Women

“…The biostatistical analysis and computational algorithms were performed using computational 'R Programming Scripts' (version R-4.0.2, for Linux) [39,40] and 'GraphPad Prism' (version 8.1.2, for Mac OS) [41,42,43] premium software packages.…”