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In silico prediction of a new lead compound targeting enolase of trypanosomatids through structure-based virtual screening and molecular dynamic studies

Abstract

Enolase is one of the key glycolytic metalloenzyme in many organisms, and it is a potential therapeutic target including trypanosomatids. Sequence and structural analysis of enolase of Trypanosoma bruzi (TbENO), Trypanosoma cruzi (TcENO) and Leishmania donovani (LdENO) revealed conserved sequence pattern and structural features. Hence identification of an inhibitor against enolase of one trypanosomatid organism may have similar effects on enolase of homologous organisms belonging to same family. In the process to identify potent inhibitor compounds against TbENO by in silico methods, compounds containing the substructures of substrate, i.e. phosphoenolpyruvate (PEP) and the well-known inhibitors, fluoro-2-phosphono-acetohydroxamate (FPAH) and phosphono-acetohydroxamate (PAH), were collected. Virtual screening and induced fit docking studies were carried out to explore compounds that have better binding affinity than PEP and FPAH. PPPi was found to be the top hit exhibiting significant binding affinity towards enolase. Glide energy values of two other compounds represented by PubChem ID: 511392 and 101803456 was in good agreement with PEP and PAH. TbENO-PPPi complex was subjected to molecular orbital analysis and molecular dynamic studies by considering its remarkable binding affinity as it could be a potent inhibitor of enolase. Despite being an endogenous compound, based on the results of this study, we highlight PPPi to be a lead compound, and its structure can be treated as a model for further chemical modifications to obtain more potent antagonists.

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Funding

KP gratefully acknowledges the Department of Biotechnology (DBT), Government of India for the financial support in the form of grants (No.BT/273/NE/TBP/2011) under North Eastern Region Twinning Programme. KP thanks DST-FIST, Government of India for computing facility sanctioned to the department (No: SR/FST/LSII-037/2014 (C) dt.29.03.2016). VMV thanks DBT for the fellowship. Dr. BSL acknowledges the financial support of the DBT – BUILDER (BT/PR12153/INF/22/200/2014) programme for the computational resources and the HPC computing facility at Anna University.

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Correspondence to Karthe Ponnuraj.

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Vidhya, V.M., Lakshmi, B.S. & Ponnuraj, K. In silico prediction of a new lead compound targeting enolase of trypanosomatids through structure-based virtual screening and molecular dynamic studies. J Mol Model 26, 23 (2020). https://doi.org/10.1007/s00894-019-4284-0

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Keywords

  • Enolase
  • Trypanosomatids
  • Virtual screening
  • Enolase inhibitor
  • PPPi
  • Molecular dynamic simulation