Exploring the antimicrobial potential of Azadirachta indica (Neem) phytoconstituents against drug-resistant Acinetobacter baumannii: A molecular docking and ADMET screening study

Abstract

Background: The emergence of multidrug resistant (MDR) Acinetobacter baumannii remains at the top of the health care concern around the world which thereby emphasizes the need to discover novel antimicrobials from medicinal plants, such as Azadirachta indica (Neem) in treatment of infections caused by MDR A. baumannii. The current in silico study was aimed to evaluate inhibitory potential of Neem derived phytoconstituents against essential proteins of A. baumannii and their evaluation of pharmacokinetic characteristics.Methodology: Selected bioactive constituents of A. indica extracted from proteomic databases were subjected to systematic molecular docking protocol (using Auto Dock Vina in PyRx interface) against three important A. baumannii protein targets; 4Y0A, 5YDB and 4DXV crystallographic structures extracted from PubChem database. The resulting binding affinity values along with detailed insights into the landscape of ligand-protein interactions provided information on the inhibitory potential of each compound. Thereafter, the highest-ranking candidates by their docking values were subjected to ADMET profiling (using ADMETlab 3.0), which entailed evaluation of absorption, distribution, metabolism, excretion, and toxicity (ADMET), in silico to assess their pharmaceutical suitability and prospective clinical application.Results: Through rigorous molecular docking studies, several phytochemicals were extracted from A. indica proteomic databases, which exhibited significant high binding affinities against the three key proteins targets of A. baumannii. Among these, isonimocinolide, nicotiflorin, and nimbaflavone showed the highest activity with binding energy ranging from -8.7 to -9.9 (kcal/mol), thus suggesting significant potential for inhibition. However, assessments of ADMET profile indicated major limitations of the pharmacokinetic and toxicological nature. Although the metabolic interactions obtained were acceptable for some of the compounds, in silico predictions suggest considerably low oral bioavailability for the three phytochemical compounds. Furthermore, toxicological screening outlined possible hepatotoxic as well as genotoxic effects.Conclusion: In this in silico study, computational analysis showed that some A. indica phytoconstituents have significant inhibitory activity against MDR A. baumannii protein targets. However, low oral bioavailability, and large tolerance risk such as liver damage and genotoxicity, indicate the need for improvement in the structures of the phytochemicals. Although these Neem derived phytochemicals show promising inhibitory activity, systematic optimization with rigorous in vitro validation will be necessary to improve their safety profiles and therapeutic efficacy.