Computational screening and MM/GBSA-based MD simulation studies reveal the high binding potential of FDA-approved drugs against Cutibacterium acnes sialidase.

Cutibacterium 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 (Δ G ) -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. Sarma.