Identification of new pharmacophore against SARS-CoV-2 spike protein by multi-fold computational and biochemical techniques

• Published in: Scientific reports Vol. 14; no. 1; p. 3590
• Main Authors: 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, Rene, Khan, Ajmal, Al-Harrasi, Ahmed
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-02-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114; 631/92; Allergenicity; Bioassays; Boswellic acid; COVID-19; Drug development; Free energy; Humanities and Social Sciences; In-vitro assay; Molecular docking; Molecular dynamics; multidisciplinary; Pharmacokinetics; Protein folding; Proteins; SARS CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike protein; Therapeutic targets; Toxicity; SARS CoV-2; Spike protein; In-vitro assay; Molecular docking; Boswellic acid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-53911-6

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 ΔG
TOTAL
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.