Rational Lead Optimization Based on the Modeled Structure of Cysteine Protease of Leishmania donovani

In present study, the molecular modeling techniques were applied to generate a refined model of a cysteine protease of Leishmania donovani using the crystal structure of a homologous protease and used for lead optimization. The structures of a series of complexes of the protease with the designed inhibitors were predicted using a novel docking technique comprising of repeated cycles of molecular dynamics and energy minimization. Calculation of the free energies of binding of the model with the designed inhibitors suggested that three compounds can form stable complexes with dissociation constants in the nanomolar range (0.038-1.41 nM). Search in the human genome revealed that a number of proteases of the cathepsin family had high homology with the parasite protease with amino acid identity around 45 %. The X-ray structures of all these were available in the protein data bank. The structures of the complexes of the selected inhibitors with a few homologous human proteases of known 3-D structures were also predicted using the same technique of optimization. The electrostatic potentials around the binding sites of the proteases were highly negative, which served as a clue for the introduction of positively charged groups in the designed inhibitors for higher affinity. The comparison of interaction energies and hydrogen bonding patterns among these complexes and similar complexes with homologous human proteases allowed us to short-listed three molecules as effective antileishmanial cysteine protease inhibitors.