Structure-based identification of inhibitory compounds targeting M32 metallocarboxypeptidase of Leishmania donovani.

Leishmaniasis remains a major public health burden due to limited vaccines, toxic treatments, and drug resistance. The M32 metallocarboxypeptidase of Leishmania donovani (LdMCP1) represents a promising target due to its presence in trypanosomatids and absence in mammals. In this study, an in silico strategy was applied to predict the three-dimensional structure of LdMCP1, revealing a canonical α/β topology and the characteristic catalytic motifs of the M32 family. Dimeric interface analysis indicated that the N-terminal subdomain plays a critical role in inter-subunit interactions and overall dimer stability. Molecular docking delineated the binding mode of a peptide substrate within the active site, highlighting key interactions with catalytic residues. Virtual screening of GSK anti-kinetoplastid libraries identified three compounds as lead molecules based on docking scores, substrate interaction patterns, and previously reported in vitro inhibitory activity against TcMCP1. These compounds exhibited favourable physicochemical properties, ADMET and pharmacokinetic profiles. All protein-ligand complexes demonstrated structural integrity, compactness, and flexibility during the molecular dynamics simulations. MM-PBSA binding free energy calculations indicated TCMDC-143515 and TCMDC-143620 bind more strongly than the substrate. Collectively, these findings suggest that LdMCP1 is a druggable enzyme and identified lead molecules provide a rational starting point for the design and optimization of specific antileishmanial agents.