Mechanistic insights into the dual inhibition strategy for checking Leishmaniasis

• Published in: Journal of biomolecular structure & dynamics Vol. 30; no. 4; pp. 474 - 487
• Main Authors: Grover, Abhinav, Katiyar, Shashank Prakash, Jeyakanthan, Jeyaraman, Dubey, Vikash Kumar, Sundar, Durai
• Format: Journal Article
• Language: English
• Published: England Routledge 01-01-2012
• Subjects: Antiprotozoal Agents - chemistry; Catalytic Domain; Citrinin - analogs & derivatives; Citrinin - chemistry; Drug Discovery; dual inhibition; Enzyme Inhibitors - chemistry; Heterocyclic Compounds, 3-Ring - chemistry; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Kinetics; Leishmania donovani; Leishmania donovani - chemistry; Leishmania donovani - enzymology; leishmaniasis; Libraries, Digital; molecular dynamics; Molecular Dynamics Simulation; molecular modeling; ornithine decarboxylase; Ornithine Decarboxylase - chemistry; Ornithine Decarboxylase Inhibitors; Polyamines - metabolism; Protein Binding; Protein Conformation; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Small Molecule Libraries - chemistry; spermidine synthase; Spermidine Synthase - antagonists & inhibitors; Spermidine Synthase - chemistry; Thermodynamics; Tryptophan - chemistry
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2012.682212

Leishmaniasis
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These authors contributed equally.
is an endemic disease mainly caused by the protozoan Leishmania donovani (Ld). Polyamines have been identified as essential organic compounds for the growth and survival of Ld. These are synthesized in Ld by polyamine synthesis pathway comprising of many enzymes such as ornithine decarboxylase (ODC), spermidine synthase (SS), and S-adenosylmethionine decarboxylase. Inhibition of these enzymes in Ld offers a viable prospect to check its growth and development. In the present work, we used computational approaches to search natural inhibitors against ODC and SS enzymes. We predicted three-dimensional structures of ODC and SS using comparative modeling and molecular dynamics (MD) simulations. Thousands of natural compounds were virtually screened against target proteins using high throughput approach. MD simulations were then performed to examine molecular interactions between the screened compounds and functional residues of the active sites of the enzymes. Herein, we report two natural compounds of dual inhibitory nature active against the two crucial enzymes of polyamine pathway of Ld. These dual inhibitors have the potential to evolve as lead molecules in the development of antileishmanial drugs.