Molecular Docking and ADMET Profiling of Tinospora cordifolia Phytochemicals Against Dihydrofolate Reductase: An Integrated in Silico Docking, Drug-Likeness, DFT, and Molecular-Dynamics Prioritization Study

Abstract

Background: Dihydrofolate reductase (DHFR) is a validated target in cancer, bacterial, and protozoal chemotherapy, but classical antifolates such as methotrexate are limited by toxicity and resistance. Tinospora cordifolia (Guduchi), a climber central to Ayurveda and the traditional medicine of South India, is a rich source of alkaloids, diterpenoid glycosides, and flavonoids that merit evaluation as alternative DHFR-binding scaffolds. Objective: To computationally screen and prioritize twelve T. cordifolia phytoconstituents as DHFR inhibitors using molecular docking, drug-likeness and ADMET prediction, density functional theory (DFT), and molecular-dynamics (MD) analysis, benchmarked against methotrexate. Methods: Twelve phytochemicals and the reference inhibitor were docked into the DHFR active site (five poses each; best binding energy retained). Drug-likeness (Lipinski), ADMET descriptors, and DFT frontier-orbital parameters were computed, and three top complexes underwent 100-ns MD with MM-GBSA free-energy estimation, feeding a tiered priority ranking. Results: Methotrexate showed the strongest predicted binding (−9.34 kcal/mol). Among phytochemicals, cordifolioside A (−8.77 kcal/mol), cordifolioside B (−8.65 kcal/mol), berberine (−8.43 kcal/mol), and tinocordiside (−8.43 kcal/mol) ranked highest, engaging conserved residues (Ile5, Val8, Ala9, Asp27, Phe31, Lys32, Arg57, Ile94, Tyr100, Thr113). Berberine combined competitive binding with the most favourable drug-likeness (zero Lipinski violations, high gastrointestinal absorption, AMES-negative). Tinocordiside displayed the smallest HOMO–LUMO gap (3.095 eV). MD confirmed stable complexes, with cordifolioside A showing the most favourable MM-GBSA free energy (−46.98 kcal/mol) and 52.2% hydrogen-bond occupancy. Conclusion: Berberine and cordifolioside A emerge as leading T. cordifolia-derived candidate DHFR binders warranting biochemical validation.