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Modeling and simulation study to identify threonine synthase as possible drug target in Leishmania major

Abstract

Leishmaniasis is one of the most neglected tropical diseases that demand immediate attention to the identification of new drug targets and effective drug candidates. The present study demonstrates the possibility of using threonine synthase (TS) as a putative drug target in leishmaniasis disease management. We report the construction of an effective homology model of the enzyme that appears to be structurally as well as functionally well conserved. The 200 nanosecond molecular dynamics data on TS with and without pyridoxal phosphate (PLP) shed light on mechanistic details of PLP-induced conformational changes. Moreover, we address some important structural and dynamic interactions in the PLP binding region of TS that are in good agreement with previously speculated crystallographic estimations. Additionally, after screening more than 44,000 compounds, we propose 10 putative inhibitor candidates for TS based on virtual screening data and refined Molecular Mechanics Generalized Born Surface Area calculations. We expect that structural and functional dynamics data disclosed in this study will help initiate experimental endeavors toward establishing TS as an effective antileishmanial drug target.

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Abbreviations

ApoTS:

Apo form of leishmanial threonine synthase

CHARMM:

Chemistry at Harvard Macromolecular Mechanics

FDA:

Food and Drug Association

GROMACS:

GROningen machine for chemical simulations

HSK:

Homoserine kinase

LGA:

Lamarckian genetic algorithm

MD:

Molecular dynamics

MM-GBSA:

Molecular Mechanics Generalized Born Surface Area

MSA:

Multiple sequence alignment

NAMD:

Nanoscale molecular dynamics

NCBI:

National Center for Biotechnology Information

NVE:

Ensemble-constant-energy, constant-volume, constant particle ensemble

OPLS:

Optimized potential for liquid simulations

PDB:

Protein data bank

PDB-ID:

Protein data bank identifier

pdbqt:

Protein data bank, partial charge (Q) and atom type (T)

PHS:

Phospho-homoserine

PLP:

Pyridoxal phosphate

PME:

Particle mesh Ewald

psf:

Protein structure file

PyRX:

Python prescription

RMSD:

Root-mean-square deviation

RMSF:

Root-mean-square fluctuation

SAVES server:

Structure analysis and verification server

SPDBV:

Swiss PDB viewer

SSB:

Sodium stibogluconate

TIP3:

Three-site-transferrable intermolecular potential

TS-PLP:

Leishmanial threonine synthase and pyridoxal phosphate complex

UFF:

Universal force field

VL:

Visceral leishmaniasis

VMD:

Visual molecular dynamics

VSGB:

Variable dielectric surface generalized born model

WHO:

World Health Organization

TS:

Threonine synthase

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Acknowledgements

We sincerely thank Dr. Sangeeta Sawant, Director, Bioinformatics Centre, Savitribai Phule Pune University, Pune, for providing infrastructure and support throughout the project. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Meshram, R.J., Bagul, K.T., Aouti, S.U. et al. Modeling and simulation study to identify threonine synthase as possible drug target in Leishmania major. Mol Divers 25, 1679–1700 (2021). https://doi.org/10.1007/s11030-020-10129-8

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Keywords

  • Threonine synthase
  • Molecular Mechanics Generalized Born Surface Area
  • Molecular dynamics simulations
  • Virtual screening
  • Pyridoxal phosphate
  • Homology modeling