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Investigation into in silico and in vitro approaches for inhibitors targeting MCM10 in Leishmania donovani: a comprehensive study

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Abstract

Visceral Leishmaniasis (VL), the second neglected tropical disease caused by various Leishmania species, presents a significant public health challenge due to limited treatment options and the absence of vaccines. The agent responsible for visceral leishmaniasis, also referred to as “black fever” in India, is Leishmania donovani. This study focuses on L. donovani Minichromosome maintenance 10 (LdMcm10), a crucial protein in the DNA replication machinery, as a potential therapeutic target in Leishmania therapy using in silico and in vitro approaches. We employed bioinformatics tools, molecular docking, and molecular dynamics simulations to predict potential inhibitors against the target protein. The research revealed that the target protein lacks homologues in the host, emphasizing its potential as a drug target. Ligands from the DrugBank database were screened against LdMcm10 using PyRx software. The top three compounds, namely suramin, vapreotide, and pasireotide, exhibiting the best docking scores, underwent further investigation through molecular dynamic simulation and in vitro analysis. The observed structural dynamics suggested that LdMcm10-ligand complexes maintained consistent binding throughout the 300 ns simulation period, with minimal variations in their backbone. These findings suggest that these three compounds hold promise as potential lead compounds for developing new drugs against leishmaniasis. In vitro experiments also demonstrated a dose-dependent reduction in L. donovani viability for suramin, vapreotide, and pasireotide, with computed IC50 values providing quantitative metrics of their anti-leishmanial efficacy. The research offers a comprehensive understanding of LdMcm10 as a drug target and provides a foundation for further investigations and clinical exploration, ultimately advancing drug discovery strategies for leishmaniasis treatment.

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Acknowledgements

Deep Bhowmik acknowledges the financial support of ICMR (Fellowship/95/2022-ECD-II, dated 17/05/2022, respectively). Satabdi Saha recognizes the financial support from the Inspire Fellowship (IF180806).

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  1. Department of Microbiology, Assam University, Silchar, 788011, Assam, India

    Satabdi Saha, Deep Bhowmik & Diwakar Kumar

  2. Department of Computational Sciences, Central University of Punjab, Bathinda, 151401, Punjab, India

    Anupama Sharma

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" SS, DB, AS and DK carried out the experiment. SS, DB and DK wrote the manuscript. SS, DB, AS and DK contributed to the analysis of the results. DK supervised the project and conceived the original idea."

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Saha, S., Sharma, A., Bhowmik, D. et al. Investigation into in silico and in vitro approaches for inhibitors targeting MCM10 in Leishmania donovani: a comprehensive study. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10876-y

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