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There is an urgent need to discover and develop novel drugs to combat Mycobacterium tuberculosis , the causative agent of tuberculosis (TB) in humans. Alkaloids have been shown to have wide-ranging therapeutic application and could be ideal candidates for drug development, and research is underway to develop new anti-tubercular drugs from natural sources. In this regard, the current research deals with finding novel lead compounds from the Withania somnifera (WS) plant. Broad health benefits of WS are due to the presence of diverse chemical constituents which include anaferine and anahygrine and which belong to the alkaloid family. In the present study, these two compounds have been theoretically studied to understand their electronic properties using the density functional theory (DFT) at the B3LYP/6-311 + G (d,p) level. HOMO and LUMO properties and molecular electrostatic potential (MEP) surface were calculated. Further, to understand the mechanism of action of these compounds and to identify their putative drug target, molecular docking and dynamics studies were employed against Mycobacterium tuberculosis dihydrofolate reductase (DHFR). It was determined that NADP + affects stability of the complexes by reducing fluctuations of residues 14-23 and 117-126. It was also found that Ile5 and Gln28 play an important role in complexation. Electron density analysis (using the AlteQ method) of the intermolecular region, analyzing both the anaferin-NADP + and anahygrin-NADP + complexes showed that anaferin and anahygrin complexes are more stable in the presence of NADP + . It has been established that in most intermolecular contacts the contribution of the ligand to the electron density is greater than that of NADP + . The present study thus provides an excellent way to analyze the effect of anaferine and anahygrine in essential processes of M. tuberculosis .Communicated by Ramaswamy H. Sarma.