Pharmacophore-guided virtual screening and dynamic simulation of Kallikrein-5 inhibitor: Discovery of potential molecules for rosacea therapy

Abstract

Rosacea is a common chronic inflammatory skin disease characterized by flushing, transient erythema, persistent erythema, telangiectasia, papules, pustules, phymata, edema, pain, stinging, or burning, and its treatment is still being developed. Rosacea is known to be regulated by excessive activation of Kallikrein-5 (KLK5). This research aimed to discover potent compounds for rosacea therapy based on virtual screening guided by pharmacophore and molecular dynamic simulation targeting KLK5. First, we generated and validated the pharmacophore model for target using the model to screen the compounds from the ZINC database and then conducted molecular docking and molecular dynamic simulations on KLK5. The generated pharmacophore model of KLK5 inhibitor has several features, such as F1: aromatic, F2: aromatic, F3: aromatic, F4: aromatic and hydrophobic, and F5: hydrogen bonding acceptors and donors. Subsequently, we used the pharmacophore model to screen the ZINC database and obtained 102 hits. Six best hits were obtained based on the docking score of KLK5, and the molecular interactions were revealed. Furthermore, the molecular dynamic simulation was conducted for 50 ns, and the system stability was assessed via RMSD, RMSF, MM-PBSA binding free energy, Rg, SASA, and PCA analyses. ZINC000022339916 was found to exhibit better stability compared with other hit compounds, azelaic acid, and native ligand of co-crystal KLK5 inhibitor. The compound is currently in the ordering process, and the study of biological activity will be held and reported soon.

Keywords

• Kallikrein-5
• Molecular dynamics
• Pharmacophore
• Rosacea
• Virtual screening