Quantum‐Chemical Evaluation of the Interaction Between the Mycobacterium tuberculosis Dihydrofolate Reductase Enzyme With Classical and Potential Inhibitors

Tuberculosis (TB) remains a major global threat, demanding new therapeutic strategies. Dihydrofolate reductase (DHFR), essential for cell survival and a known drug target, has emerged as a promising enzyme for anti-TB drug development. Using crystallographic structures of Mycobacterium tuberculosis DHFR (MtDHFR) complexed with classical and potential inhibitors, a quantum-chemical analysis was performed through the molecular fractionation with conjugate caps (MFCC) scheme within the density functional theory (DFT) framework to quantify individual amino acid contributions to ligand-protein interactions. Energetically significant interactions were observed within a 6.0 Å pocket, when convergence of the total interaction energy (TIE) was found. The key residues I5, W6, D19, I20, R23, D27, Q28, H30, F31, R32, L50, K53, L57, R60, I94, and E111 were identified, along with the energetically relevant regions of the ligands and the major secondary structures of the protein. These results may guide the design of new anti-TB drugs.