A computational study exploring echinoderm-derived compounds for inhibition of aminoglycoside acetyltransferases

Abstract

Aminoglycoside acetyltransferases (AACs) catalyze the acetylation of aminoglycoside antibiotics, playing a major role in bacterial resistance and posing a serious threat to global healthcare. Despite growing interest in natural products, echinoderm-derived metabolites remain largely unexplored as AAC inhibitors. This study presents a comprehensive in-silico investigation into the potential of these marine compounds to inhibit four key AAC enzymes: Aminoglycoside 2′-N-acetyltransferase, AAC(3)-Ib, AAC(6′)-Im, and AAC(3)-Iva. A virtual screening of 1600 echinoderm metabolites was performed using molecular docking, ADMET profiling, and 100 ns molecular dynamics simulations. The top 10 compounds against each enzyme were shortlisted based on binding affinity, with CMNPD15515, CMNPD17440, CMNPD3088, and CMNPD29853 showing the most stable interactions and highest binding energies. These compounds consistently outperformed native aminoglycoside ligands in docking scores and MMGBSA binding free energy calculations, suggesting stronger inhibitory potential. While a few top hits exhibited violations of Lipinski’s Rule of Five particularly in molecular weight their strong target engagement and stable dynamic profiles support their candidacy as lead molecules. This work underscores the evolutionary and structural uniqueness of echinoderm metabolites as a promising reservoir for antibiotic adjuvants. It also establishes a computational framework for prioritizing marine natural products against antibiotic resistance targets. Although experimental validation remains essential, this study provides compelling early evidence to guide future in vitro and in vivo research toward the development of novel AAC inhibitors.