Mechanistic insights into the dual inhibition strategy for checking Leishmaniasis.
Leishmaniasis  (1)   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.    (1)These authors contributed equally.
Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, 110016, India.
Abhinav
A
Grover
Shashank Prakash
SP
Katiyar
Jeyaraman
J
Jeyakanthan
Vikash Kumar
VK
Dubey
Durai
D
Sundar
D000981:Antiprotozoal Agents / Q000737:chemistry; D020134:Catalytic Domain; D002953:Citrinin / Q000031:analogs & derivatives* / Q000737:chemistry; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D007893:Leishmania donovani / Q000737:chemistry* / Q000201:enzymology; D046609:Libraries, Digital; D056004:Molecular Dynamics Simulation; D009955:Ornithine Decarboxylase / Q000737:chemistry; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry / Q000031:analogs & derivatives
C576612:2-((1)benzofuro(3,2-d)pyrimidin-4-ylamino)-3-(1H-indol-3-yl)propanoate; D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; D002953:Citrinin; C015142:dihydrocitrinone; D014364:Tryptophan; D011436:Spermidine Synthase; D009955:Ornithine Decarboxylase