Molecular Modeling and Virtual Screening Approach to Discover Potential Antileishmanial Inhibitors Against Ornithine Decarboxylase.
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.


RESULTS
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.
Rajan Kumar
RK
Pandey
Priyanka
P
Prajapati
Sukriti
S
Goyal
Abhinav
A
Grover
Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Kishangarh 305817, Ajmer, Rajasthan, India.. India.
Vijay Kumar
VK
Prajapati
D000595:Amino Acid Sequence; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D007893:Leishmania donovani / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D009955:Ornithine Decarboxylase / Q000737:chemistry / Q000187:drug effects*; D065108:Ornithine Decarboxylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
D000981:Antiprotozoal Agents; D065108:Ornithine Decarboxylase Inhibitors; D009955:Ornithine Decarboxylase
Leishmaniasis; antileishmanial; molecular docking; molecular dynamics; molecular modeling; ornithine
decarboxylase.