Pharmacophore-guided drug design using LdNMT as a model drug target for leishmaniasis

Leishmaniasis is caused by <i>Leishmania</i> genus parasites and has a high mortality rate. The available drugs to treat leishmaniasis fail due to acquired resistance in parasites. Several enzymes of the <i>Leishmania</i> parasite have been used to design new therapeutic molecules against leishmaniasis. This study uses a pharmacophore-guided approach to design the drug candidate by targeting <i>Leishmania</i> N-Myristoyl transferase (LdNMT). From the initial sequence analysis of LdNMT, we have identified a unique 20 amino acid stretch exploited for screening and designing the small molecules. The pharmacophore for the myristate binding site on LdNMT was elucidated, and a heatmap was constructed. The leishmanial NMT pharmacophore has similarities with other pathogenic microorganisms. Moreover, substituting alanine in pharmacophoric residues elevates the affinity of myristate with NMT. Furthermore, a molecular dynamics (MD) simulation study was conducted to ascertain the stability of the mutants and or wild type. The wild-type NMT has a comparatively low affinity to myristate compared to alanine mutants, indicating that hydrophobic residues favor the myristate binding. The molecules were initially designed by using pharmacophore as a sieving mechanism. In subsequent steps, the selected molecules screened against leishmanial unique amino acid stretch and subsequently with human, leishmanial full-size NMTs. The compounds BP5, TYI, DMU, 3PE and 4UL were the top hits and chemical features similar to the myristate. The molecule 4UL was found to be highly specific towards leishmanial NMT over human NMT, suggesting the molecule is a strong leishmanial NMT inhibitor. The molecule can be taken further to assess it in in-vitro conditions.