Functional Annotation Identifies 3-Oxoacyl Synthase III as a Druggable Target in Nocardia asteroides FDAARGOS1485: A Multi-Tier Structure-Guided Computational Discovery of Marine-Derived Therapeutic Leads.

Nocardiosis is a global life-threatening disease that predominantly affects immunodeficient populations. This disease is caused by the nosocomial pathogen Nocardia asteroides. Existing therapeutics offer several limitations and challenges, highlighting the need for novel druggable targets. The pathogenic strain FDAARGOS1485 contains 6,521 proteins and has a higher completeness of 98%, as determined by CheckM analysis. Among these proteins, 863 (13.20%) hypothetical proteins (HPs) were designated as targets. The functional annotation pipeline identified 30 (4.40%) HPs, classified into 24 enzymes (80%), 2 transporters (6.66%), 2 binding proteins (6.66%), and 2 proteins involved in cell regulatory processes (6.66%). Metabolic pathway analysis revealed the functionally annotated 3-oxoacyl-synthase III protein (WP_223513777.1) as a promising target. The structure-based virtual screening approach identified three potential MNPs (CMNPD22130, CMNPD23347, and SWMDRR052) with favourable docking scores ranging from - 8.23 to - 10.05 kcal/mol and post-docking binding energy values between - 62.42 and - 72.91 kcal/mol. Remarkably, none of the candidates violated Lipinski's rule (Ro5), and all exhibited satisfactory pharmacokinetic profiles and favourable DFT scores. Molecular dynamics and essential dynamics confirmed the stability of the MNP-bound 3-oxoacyl-synthase III complexes. Furthermore, by utilizing 40 diverse computational resources, the present study proposes potential MNPs against nocardiosis and warrants experimental validations to explore their therapeutic potential.