Computational screening and MM/GBSA-based MD simulation studies reveal the high binding potential of FDA-approved drugs againstCutibacterium acnessialidase

AbstractCutibacterium acnes is an opportunistic pathogen linked with acne vulgaris, affecting 80–90% of teenagers globally. On the leukocyte (WBCs) cell surface, the cell wall anchored sialidase in C. acnes virulence factor, catalysing the sialoconjugates into sialic acids and nutrients for C. acnes resulting in human skin inflammation. The clinical use of antibiotics for acne treatments has severe adverse effects, including microbial dysbiosis and resistance. Therefore, identifying inhibitors for primary virulence factors (Sialidase) was done using molecular docking of 1030 FDA-approved drugs. Initially, based on binding energies (ΔG), Naloxone (ZINC000000389747), Fenoldopam (ZINC000022116608), Labetalol (ZINC000000403010) and Thalitone (ZINC000000057255) were identified that showed high binding energies as −10.2, −10.1, −9.9 and −9.8 kcal/mol, respectively. In 2D analysis, these drugs also showed considerable structural conformer of hydrogen and hydrophobic interactions. Further, a 100 ns MD simulation study found the lowest deviation and fluctuations with various intermolecular interactions to stabilise the complexes. Out of 4, the Naloxone molecule showed robust, steady, and stable RMSD 0.23 ± 0.18 nm. Further, MMGBSA analysis supports MD results and found strong binding energy (ΔG) −29.71 ± 4.97 kcal/mol. In Comparative studies with Neu5Ac2en (native substrate) revealed naloxone has a higher affinity for sialidase. The PCA analysis showed that Naloxone and Thalitone were actively located on the active site, and other compounds were flickered. Our extensive computational and statistical report demonstrates that these FDA drugs can be validated as potential sialidase inhibitors.Communicated by Ramaswamy H. SarmaKeywords: Cutibacterium acnessialidaseMMGBSAdensity function theorymolecular dynamics simulation AcknowledgementsThe author is greatly acknowledged and thankful to the director of CSIR-IGIB for providing the research facility and carrying out research work and Jamia Millia Islamia for providing computational and other support for smooth work.Availability of data and materialAll the data in supplementary material provided for extended validation or analysis produced during the docking phase can be made public after publication.Authors' contributionsConceptualisation, data collection/curation, analysis, writing, reviewing the first draft: Akash Pratap Singh. Conceptualisation, data collection/curation, analysis, writing, reviewing and editing the first draft: Shaban Ahmad. Computational resources, reviewing, editing the first draft: Hemant K. Gautam. Computational resources, reviewing and editing: Khalid Raza.Consent for publicationAll authors consent to submit the manuscript to the journal.Disclosure statementNo potential conflict of interest was reported by the author(s).Ethical responsibilitiesThis study does not directly involve humans or other organisms.Additional informationFundingThe author (APS) received a Senior Research Fellowship (31/0430410)/2019-EMR-I) from the Council of Scientific & Industrial Research (CSIR), India.