Evaluation of potential drugs against leishmaniasis targeting catalytic subunit of Leishmania donovani nuclear DNA primase using ligand based virtual screening, docking and molecular dynamics approaches

Abstract

Leishmania donovani, causes leishmaniasis, a global health trouble with around 89 different countries and its population under its risk. Replication initiation events have been instrumental in regulating the DNA duplication and as the small subunit of L. donovani nuclear DNA primase (Ld-PriS) inherits the catalytic site, it plays a vital role in DNA replication. In this study we have aimed Ld-PriS for the first time as a prospective target for the application of drug against Leishmania parasite. 3-D structures of Ld-PriS were built and ligand-based virtual screening was performed using hybrid similarity recognition techniques. Ligands from the ZINC database were used for the screening purposes based on known DNA primase inhibitor Sphingosine as a query. Top 150 ligands were taken into consideration for molecular docking against the query protein (Ld-PriS) using PyRx and iGEMDOCK softwares. Top five compounds with the best docking score were selected for pharmacokinetic investigation and molecular dynamic simulation. These top five screened inhibitors showed very poor binding affinity toward the catalytic subunit of human primase indicating their safety toward the host normal replication mechanism. The top five compounds showed good pharmacokinetic profiles and ADMET predictions revealed good absorption, solubility, permeability, uniform distribution, proper metabolism, minimal toxicity and good bioavailability. Simulation studies upto 50 ns revealed the three leads ZINC000009219046, ZINC000025998119 and ZINC000004677901 bind with Ld-PriS throughout the simulation and there were no huge variations in their backbone suggesting that these three may play as potential lead compounds for developing new drug against leishmaniasis.

Communicated by Ramaswamy H. Sarma

Keywords:

• Leishmaniasis
• DNA replication
• DNA primase
• virtual screening
• molecular docking
• molecular dynamic simulation
• ADMET

Disclosure statement

The authors declare that no conflict of interest exists.

Table 3. Docking results of top five ligands against small subunit of nuclear DNA Primase of Leishmania donovani performed by iGEMDOCK tool.

Additional information

Funding

Lab is supported by SERB-ECR, GOI grant (FILE NO. ECR/2015//000155) and DBT-Twinning, GOI grant (GOI) (order no: BT/PR16224/NER/95/176/2015) to Dr. Diwakar Kumar. Deep Bhowmik received funding from the SERB-ECR, GOI grant (FILE NO. ECR/2015//000155).