title: Blocking protein kinase C signaling pathway: mechanistic insights into the anti-leishmanial activity of prospective herbal drugs from Withania somnifera.
abstract: BACKGROUND
  Leishmaniasis is caused by several species of leishmania protozoan and is one of the major vector-born diseases after malaria and sleeping sickness. Toxicity of available drugs and drug resistance development by protozoa in recent years has made Leishmaniasis cure difficult and challenging. This urges the need to discover new antileishmanial-drug targets and antileishmanial-drug development.
  
  
  RESULTS
  Tertiary structure of leishmanial protein kinase C was predicted and found stable with a RMSD of 5.8Å during MD simulations. Natural compound withaferin A inhibited the predicted protein at its active site with -28.47 kcal/mol binding free energy. Withanone was also found to inhibit LPKC with good binding affinity of -22.57 kcal/mol. Both withaferin A and withanone were found stable within the binding pocket of predicted protein when MD simulations of ligand-bound protein complexes were carried out to examine the consistency of interactions between the two.
  
  
  CONCLUSIONS
  Leishmanial protein kinase C (LPKC) has been identified as a potential target to develop drugs against Leishmaniasis. We modelled and refined the tertiary structure of LPKC using computational methods such as homology modelling and molecular dynamics simulations. This structure of LPKC was used to reveal mode of inhibition of two previous experimentally reported natural compounds from Withania somnifera - withaferin A and withanone.
authors.affiliation: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
authors.forename: Shashank Prakash
authors.initials: SP
authors.lastname: Katiyar
authors.forename: Jeyaraman
authors.initials: J
authors.lastname: Jeyakanthan
authors.forename: Vikash Kumar
authors.initials: VK
authors.lastname: Dubey
authors.forename: Durai
authors.initials: D
authors.lastname: Sundar
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D029001:Herbal Medicine; D007891:Leishmania / Q000378:metabolism; D062105:Molecular Docking Simulation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013816:Thermodynamics; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D032341:Withania / Q000737:chemistry*; D054358:Withanolides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D014315:Triterpenes; D054358:Withanolides; D011493:Protein Kinase C; C560597:withanone; C009684:withaferin A