AUTHOR=Hosen Md. Eram , Jahan Supti Sumaiya , Akash Shopnil , Rahman Md. Ekhtiar , Faruqe Md Omar , Manirujjaman M. , Acharjee Uzzal Kumar , Gaafar Abdel-Rhman Z. , Ouahmane Lahcen , Sitotaw Baye , Bourhia Mohammed , Zaman Rashed TITLE=Mechanistic insight of Staphylococcus aureus associated skin cancer in humans by Santalum album derived phytochemicals: an extensive computational and experimental approaches JOURNAL=Frontiers in Chemistry VOLUME=11 YEAR=2023 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2023.1273408 DOI=10.3389/fchem.2023.1273408 ISSN=2296-2646 ABSTRACT=

An excessive amount of multidrug-resistant Staphylococcus aureus is commonly associated with actinic keratosis (AK) and squamous cell carcinoma (SCC) by secreted virulence products that induced the chronic inflammation leading to skin cancer which is regulated by staphylococcal accessory regulator (SarA). It is worth noting that there is currently no existing published study that reports on the inhibitory activity of phytochemicals derived from Santalum album on the SarA protein through in silico approach. Therefore, our study has been designed to find the potential inhibitors of S. aureus SarA protein from S. album-derived phytochemicals. The molecular docking study was performed targeting the SarA protein of S. aureus, and CID:5280441, CID:162350, and CID: 5281675 compounds showed the highest binding energy with −9.4 kcal/mol, −9.0 kcal/mol, and −8.6 kcal/mol respectively. Further, molecular dynamics simulation revealed that the docked complexes were relatively stable during the 100 ns simulation period whereas the MMPBSA binding free energy proposed that the ligands were sustained with their binding site. All three complexes were found to be similar in distribution with the apoprotein through PCA analysis indicating conformational stability throughout the MD simulation. Moreover, all three compounds’ ADMET profiles revealed positive results, and the AMES test did not show any toxicity whereas the pharmacophore study also indicates a closer match between the pharmacophore model and the compounds. After comprehensive in silico studies we evolved three best compounds, namely, Vitexin, Isovitexin, and Orientin, which were conducted in vitro assay for further confirmation of their inhibitory activity and results exhibited all of these compounds showed strong inhibitory activity against S. aureus. The overall result suggests that these compounds could be used as a natural lead to inhibit the pathogenesis of S. aureus and antibiotic therapy for S. aureus-associated skin cancer in humans as well.