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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DOI: https://doi.org/10.1007/s11030-020-10129-8