Molecular Docking, ADMET, DFT, and Molecular-Dynamics Prioritization of Common Dietary Flavonoids as Candidate Beta-Lactamase Inhibitors: An In Silico Screening Study Relevant to Antimicrobial Resistance

Abstract

Background: Antimicrobial resistance (AMR) is among the gravest public-health threats of the twenty-first century, and bacterial beta-lactamase enzymes are a principal driver of resistance to beta-lactam antibiotics. Dietary flavonoids, abundant in the South Indian diet, are widely explored as scaffolds for adjunctive antibacterial agents. This study applied an integrated in silico workflow to prioritize common dietary flavonoids as candidate beta-lactamase inhibitors. Methods: Thirteen dietary flavonoids and the reference inhibitor clavulanic acid were docked against a bacterial beta-lactamase, generating five poses per ligand (70 docking records). Poses were profiled for binding energy and interaction patterns. Drug-likeness and ADMET properties, density-functional-theory (DFT) electronic descriptors, and 100-ns molecular-dynamics (MD) simulations with MM-GBSA free-energy estimation for three top complexes were integrated into a ranking scheme. Results: Best docking energies for flavonoids ranged from -7.59 to -8.74 kcal/mol, closely bracketing clavulanic acid (-8.88 kcal/mol). Epigallocatechin gallate (-8.74), myricetin (-8.63), and luteolin (-8.45 kcal/mol) were the strongest flavonoid binders. Ligands engaged conserved active-site residues including Ser70, Lys73, Ser130, Glu166, Asn170 and Lys234. Most flavonoids satisfied Lipinski rule with high predicted gastrointestinal absorption; luteolin combined favourable docking, zero Lipinski violations, high absorption, a negative AMES prediction and a low HOMO-LUMO gap (3.25 eV), earning the only High integrated priority. In MD, the luteolin complex showed the highest hydrogen-bond occupancy (72.5%), while MM-GBSA free energies ranged from -31.68 to -42.92 kcal/mol. Conclusions: Common dietary flavonoids, particularly luteolin and the strong binders epigallocatechin gallate and myricetin, emerge as hypothesis-generating candidate beta-lactamase inhibitors. These purely computational findings do not establish enzyme inhibition or reversal of resistance and require biochemical beta-lactamase assays and bacterial susceptibility testing for validation.