| Summary: | Leishmaniasis is a group of infectious diseases caused by <i>Leishmania</i> protozoa. The ineffectiveness, high toxicity, and/or parasite resistance of the currently available antileishmanial drugs has created an urgent need for safe and effective leishmaniasis treatment. Currently, the molecular-docking technique is used to predict the proper conformations of small-molecule ligands and the strength of the contact between a protein and a ligand, and the majority of research for the development of new drugs is centered on this type of prediction. <i>Leishmania</i> N-myristoyltransferase (NMT) has been shown to be a reliable therapeutic target for investigating new anti-leishmanial molecules through this kind of virtual screening. Natural products provide an incredible source of affordable chemical scaffolds that serve in the development of effective drugs. <i>Withania somnifera</i> leaves, roots, and fruits have been shown to contain withanolide and other phytomolecules that are efficient anti-protozoal agents against <i>Malaria, Trypanosoma</i>, and <i>Leishmania</i> spp. Through a review of previously reported compounds from <i>W. somnifera</i>-afforded 35 alkaloid, phenolic, and steroid compounds and 132 withanolides/derivatives, typical of the <i>Withania</i> genus. These compounds were subjected to molecular docking screening and molecular dynamics against <i>L. major</i> NMT. Calycopteretin-3-rutinoside and withanoside IX showed the highest affinity and binding stability to <i>L. major</i> NMT, implying that these compounds could be used as antileishmanial drugs and/or as a scaffold for the design of related parasite NMT inhibitors with markedly enhanced binding affinity.
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