In Silico Pharmacological Evaluation and ADME Profiling of Berberine and Rosmarinic Acid as Potential Inhibitors of Escherichia Coli Dihydrofolate Reductase
TL;DR
This study evaluated selected natural compounds as potential inhibitors of Escherichia coli DHFR using molecular docking followed by in silico drug-likeness and pharmacokinetic profiling and computational findings do not establish direct enzyme inhibition or antibacterial efficacy.
Abstract
Antimicrobial resistance has increased the need to identify alternative antibacterial scaffolds targeting established bacterial pathways. Dihydrofolate reductase (DHFR) is an established antimicrobial target involved in bacterial folate metabolism. This study evaluated selected natural compounds as potential inhibitors of Escherichia coli DHFR (ecDHFR) using molecular docking followed by in silico drug-likeness and pharmacokinetic profiling. Ten natural compounds were screened against ecDHFR using the CB-Dock platform, and their predicted binding scores were compared with the reference inhibitor trimethoprim. The two highest-ranked compounds were subsequently evaluated using SwissADME. Rosmarinic acid and berberine demonstrated the most favorable predicted docking scores, with Vina scores of −9.0 and −8.8 kcal/mol, respectively. Both compounds showed zero violations of Lipinski's rule of five. Rosmarinic acid demonstrated low predicted gastrointestinal absorption, whereas berberine showed high predicted gastrointestinal absorption and predicted inhibition of CYP2C9 and CYP3A4. These findings identify berberine and rosmarinic acid as natural-product scaffolds worthy of further investigation against ecDHFR. However, the computational findings do not establish direct enzyme inhibition or antibacterial efficacy. Experimental enzyme inhibition, antibacterial susceptibility, pharmacokinetic, and safety studies are required to validate these predictions.