Title:Molecular Modeling and Virtual Screening Approach to Discover Potential Antileishmanial Inhibitors Against Ornithine Decarboxylase
Volume: 19
Issue: 10
Author(s): Rajan Kumar Pandey, Priyanka Prajapati, Sukriti Goyal, Abhinav Grover and Vijay Kumar Prajapati
Affiliation:
Keywords:
Leishmaniasis, molecular docking, molecular modeling, antileishmanial, molecular dynamics, ornithine
decarboxylase.
Abstract: Background: Visceral leishmaniasis (VL) is a tropical neglected disease,
which encounters poorest of poor people living in Asia, Africa and Latin America;
causing the mortality of more than 30,000 people worldwide. The armamentarium
for the treatment of VL cases is limited and continuously facing decreasing of
efficacy for existing drugs. Ornithine decarboxylase (ODC) is one of the interesting
drug targets in Leishmania donovani, due to its association with redox metabolism.
Objective: To search an antileishmanial compound showing the inhibitory effect
against ornithine decarboxylase of Leishmania donovani
Method: In this study, we have modelled the three dimensional structure of ODC
using Phyre2 (Protein Homology/analog Y Recognition Engine V 2.0), followed by
validation using VADAR (Volume, Area, Dihedral Angle Reporter), RAMPAGE, ERRAT, Verify3D
and ProSA (Protein Structure Analysis). In order to develop potential antileishmanial, we conducted a
high throughput virtual screening of ZINC database ligands comprising of 135,966 compounds.
Furthermore, QikProp, ADMET predictor and MM-GBSA was performed for ADME (Absorption,
Distribution, Metabolism and Elimination), toxicity and binding energy prediction for top ligands,
respectively. Finally, molecular dynamics simulation was performed to get potential antileishmanial
compounds.
Result: Screening of zinc database compounds using high throughput virtual screening has given
twelve compounds with good inhibition activity against ornithine decarboxylase. Furthermore, the
molecular dynamics simulation work reveals that ZINC67909154 could be a potent inhibitor and this
compound can be used to combat VL disease
Conclusion: This study concludes that ZINC67909154 has the great potential to inhibit L. donovani
ODC and would add to the drug discovery process against visceral leishmaniasis.
