Computational approach to identify potential antileishmanial activity of reported inhibitor, E5700 and two natural alkaloids against Leishmania donovani Squalene Synthase

Abstract

Leishmania species are the causative agents for Leishmaniasis which is one of the neglected tropical diseases causing 70,000 deaths worldwide each year. Squalene synthase enzyme plays a vital role in sterol metabolism which is essential for Leishmania parasite viability. Therefore squalene synthase of Leishmania donovani is a therapeutic target to inhibit growth of parasite. The 3D model of Leishmania donovani Squalene Synthase (LdSQS) was generated by homology modeling and validated through PROCHECK, ERRAT, VERIFY3D and PROSA tools. Virtual screening of the protein was performed by AutoDock with reported inhibitor, E5700 and two natural alkaloids. Molecular interactions were explored to understand the nature of intermolecular bonds between active ligand and the protein binding site residues using UCSF Chimera and PLIP server. The reported inhibitor showed the best binding affinity (-9.75 kcal/mol) closely followed by Ancistrotanzanine B (-9.55 kcal/mol) and Holamine (-8.79 kcal/mol). Ancistrotanzanine B showed low binding energy and permissible ADMET properties. Based on the present study, homology model of LdSQS and Ancistrotanzanine B can be used to design inhibitors with antileishmanial activity.

Computational study to discover potent phytochemical inhibitors against drug target, squalene synthase from Leishmania donovani

“…In the top hit ligands, ancistrotanzanine B showed the best docking pose with the least binding energy (-9.83 kcal/mol and K i of 61.84 nM) with LdSQS closely followed by reported inhibitor 1 (E5700), ancistrotanzanine A, ancistrobenomine A, 5-epi-4 0 -O-demethylancistrobertsonine C, ancistroealaine B, ramiflorine B and 3-O-methyldiplacol with binding affinities of -9.81 kcal/ mol (Ki of 64.82 nM), -9.68 kcal/mol (K i of 80.37 nM), -9.54 kcal/mol (K i of 101.91 nM), -9.34 kcal/mol (K i of 143.41 nM), -9.32 kcal/mol (K i of 146.86 nM), -9.23 kcal/mol (K i of 171.07 nM) and -9.10 kcal/mol (K i of 213.00 nM) respectively. Interestingly, the docking scores for E5700 and ancistrotanzanine B in the current study, were slightly different than the previously published results where E5700 (-9.75 kcal/ mol) exhibited higher score than ancistrotanzanine B (-9.55 kcal/mol) [17].…”

“…Based on the methodology followed in the previously published pilot study, 50 models of the LdSQS protein was built [ 17 ]. The solved crystal structure of LdSQS is not available at the RCSB Protein Data Bank ( https://www.rcsb.org/ ) [ 24 ].…”

“…Then the selected model was refined by quality information from MolProbity server [ 26 ] using UCSF Chimera v.1.12 [ 27 ]. The selected model was energy minimized up to 2100 steps by steepest descent algorithm in AMBER force field (using UCSF Chimera) instead of 1000 steps which were carried in the previous publication [ 17 ]. This additional step not only relieved steric clashes and improper contacts of the model but also that increased the values of validation results hence improving the quality of the model.…”

“…A pilot docking study using homology modeled LdSQS with the reported inhibitor (E5700) and two plant derived alkaloids (ancistrotanzanine b and holamine) was conducted and published by the first author [ 17 ]. The promising results from the pilot study led to design a full scale computational study to explore potent inhibitors from plant derived compounds against LdSQS.…”

“…In the current study, the modeled LdSQS protein was subjected to further energy minimization using steepest descent algorithm than in the previously published model [ 17 ]. This brought significant improvement in the ERRAT and MolProbity validation results of the modeled protein thus enhancing the accuracy of the new LdSQS model.…”