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Development and application of fragment-based de novo inhibitor design approaches against Plasmodium falciparum GST

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Abstract

Context

Modulation of disease progression is frequently started by identifying biochemical pathway catalyzed by biomolecule that is prone to inhibition by small molecular weight ligands. Such ligands (leads) can be obtained from natural resources or synthetic libraries. However, de novo design based on fragments assembly and optimization is showing increasing success. Plasmodium falciparum parasite depends on glutathione-S-transferase (PfGST) in buffering oxidative heme as an approach to resist some antimalarials. Therefore, PfGST is considered an attractive target for drug development. In this research, fragment-based approaches were used to design molecules that can fit to glutathione (GSH) binding site (G-site) of PfGST.

Methods

The involved approaches build molecules from fragments that are either isosteric to GSH sub-moieties (ligand-based) or successfully docked to GSH binding sub-pockets (structure-based). Compared to reference GST inhibitor of S-hexyl GSH, ligands with improved rigidity, synthetic accessibility, and affinity to receptor were successfully designed. The method involves joining fragments to create ligands. The ligands were then explored using molecular docking, Cartesian coordinate’s optimization, and simplified free energy determination as well as MD simulation and MMPBSA calculations. Several tools were used which include OPENEYE toolkit, Open Babel, Autodock Vina, Gromacs, and SwissParam server, and molecular mechanics force field of MMFF94 for optimization and CHARMM27 for MD simulation. In addition, in-house scripts written in Matlab were used to control fragments connection and automation of the tools.

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Data availability

Available in supplementary materials. The scripts using in designing IFR fragments as well data analysis are available in supplementary material.

The full database of generated IFR and DFR fragments are available on request.

The Molinspiration fragments database were kindly provided by Dr. Macky Slimak as in attached email.

Dear Mohammed,

please find the Molinspiration collection of drug-like substituents and linkers, together with calculated properties, attached.

More details about calculated properties are available at http://www.molinspiration.com/services/properties.html.

By using the data, you agree that the data will be used purely for scientific / academic research (no industry collaborations) and will not be distributed outside your working group. We require also that Molinspiration is acknowledged in eventual presentations or publications using these data.

Be so kind and confirm, that you received the data safely.

Kind regards,

Dr. Macky Slimak

CTO, Molinspiration Cheminformatics

Code availability

Available in supplementary materials.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. College of Pharmacy, Knowledge University, Erbil, Iraq

    Mohammed Nooraldeen Mahmod Al-Qattan

  2. College of Pharmacy, Ninevah University, Mosul, Iraq

    Mohammed Nooraldeen Mahmod Al-Qattan

  3. Centre for Drug Research, Universiti sains Malaysia, 11800 USM, Pulau Pinang, Malaysia

    Mohd Nizam Mordi

Authors
  1. Mohammed Nooraldeen Mahmod Al-Qattan
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  2. Mohd Nizam Mordi
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Contributions

Dr. Mohammed Nooraldeen proposed the topic, handled research, and wrote manuscript while Prof Mohd Nizam Mordi provided consultations and manuscript reviewing.

Corresponding author

Correspondence to Mohammed Nooraldeen Mahmod Al-Qattan.

Ethics declarations

This work was supported by research fellowship program provided by Universiti Sains Malaysia. The authors have no relevant financial or non-financial interests to disclose. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Some of scripts used are avaliable on Github repository https://github.com/mohammednooraldeen.

Conflict of interest

The authors declare no competing interests.

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Al-Qattan, M.N.M., Mordi, M.N. Development and application of fragment-based de novo inhibitor design approaches against Plasmodium falciparum GST. J Mol Model 29, 281 (2023). https://doi.org/10.1007/s00894-023-05650-0

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