Abstract
BackgroundLeishmaniasis 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.ResultsTertiary 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.ConclusionsLeishmanial 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.
Highlights
Leishmaniasis is caused by several species of leishmania protozoan and is one of the major vectorborn diseases after malaria and sleeping sickness
Though withanone has not yet been tested against leishmaniasis experimentally, this study provides a computational proof of its possible inhibitory activity against Leishmanial protein kinase C (LPKC)
We analyzed the inhibitory property of withaferin A as well as that of withanone at the molecular level
Summary
Leishmaniasis is caused by several species of leishmania protozoan and is one of the major vectorborn diseases after malaria and sleeping sickness. Leishmaniasis is responsible for the death of approximately 70,000 people each year worldwide [2] It is caused by various species of intramacrophage protozoan Leishmania like Leishmania. Withaferin A has been identified as one of ashwagandha’s prominent phytocompounds It is a cell permeable steroidal lactone which has been shown to possess anti-leishmanial property [5] apart from many other pharmacological properties. Withaferin A belongs to a class of compounds from Withania somnifera collectively known as withanolides These exhibit number of other therapeutic activities like anticancer [7,8,9,10,11], anti-herpetic [12] and neuronal regeneration property [13]. Withaferin A has been reported to induce apoptosis in leishmanial cells by targeting its protein kinase [6]
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