Please use this identifier to cite or link to this item: http://dx.doi.org/10.25673/115624
Title: Identification of new pharmacophore against SARS-CoV-2 spike protein by multi-fold computational and biochemical techniques
Author(s): Ullah, Atta
Ullah, Saeed
Halim, Sobia Ahsan
Waqas, Muhammad
Ali, Basharat
Ataya, Farid S.
El-Sabbagh, Nasser M.
Batiha, Gaber El-Saber
Avula, Satya Kumar
Csuk, RenéLook up in the Integrated Authority File of the German National Library
Khan, AjmalLook up in the Integrated Authority File of the German National Library
Al-Harrasi, AhmedLook up in the Integrated Authority File of the German National Library
Issue Date: 2024
Type: Article
Language: English
Abstract: COVID-19 appeared as a highly contagious disease after its outbreak in December 2019 by the virus, named SARS-CoV-2. The threat, which originated in Wuhan, China, swiftly became an international emergency. Among different genomic products, spike protein of virus plays a crucial role in the initiation of the infection by binding to the human lung cells, therefore, SARS-CoV-2’s spike protein is a promising therapeutic target. Using a combination of a structure-based virtual screening and biochemical assay, this study seeks possible therapeutic candidates that specifically target the viral spike protein. A database of ~ 850 naturally derived compounds was screened against SARS-CoV-2 spike protein to find natural inhibitors. Using virtual screening and inhibitory experiments, we identified acetyl 11-keto-boswellic acid (AKBA) as a promising molecule for spike protein, which encouraged us to scan the rest of AKBA derivatives in our in-house database via 2D-similarity searching. Later 19 compounds with > 85% similarity with AKBA were selected and docked with receptor binding domain (RBD) of spike protein. Those hits declared significant interactions at the RBD interface, best possess and excellent drug-likeness and pharmacokinetics properties with high gastrointestinal absorption (GIA) without toxicity and allergenicity. Our in-silico observations were eventually validated by in vitro bioassay, interestingly, 10 compounds (A3, A4, C3, C6A, C6B, C6C, C6E, C6H, C6I, and C6J) displayed significant inhibitory ability with good percent inhibition (range: > 72–90). The compounds C3 (90.00%), C6E (91.00%), C6C (87.20%), and C6D (86.23%) demonstrated excellent anti-SARS CoV-2 spike protein activities. The docking interaction of high percent inhibition of inhibitor compounds C3 and C6E was confirmed by MD Simulation. In the molecular dynamics simulation, we observed the stable dynamics of spike protein inhibitor complexes and the influence of inhibitor binding on the protein’s conformational arrangements. The binding free energy ΔGTOTAL of C3 (−38.0 ± 0.08 kcal/mol) and C6E (−41.98 ± 0.08 kcal/mol) respectively indicate a strong binding affinity to Spike protein active pocket. These findings demonstrate that these molecules particularly inhibit the function of spike protein and, therefore have the potential to be evaluated as drug candidates against SARS-CoV-2.
URI: https://opendata.uni-halle.de//handle/1981185920/117579
http://dx.doi.org/10.25673/115624
Open Access: Open access publication
License: (CC BY 4.0) Creative Commons Attribution 4.0(CC BY 4.0) Creative Commons Attribution 4.0
Journal Title: Scientific reports
Publisher: Macmillan Publishers Limited, part of Springer Nature
Publisher Place: [London]
Volume: 14
Issue: 1
Original Publication: 10.1038/s41598-024-53911-6
Appears in Collections:Open Access Publikationen der MLU

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