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A structure-based virtual high-throughput screening, molecular docking, molecular dynamics and MM/PBSA study identified novel putative drug-like dual inhibitors of trypanosomal cruzain and rhodesain cysteine proteases

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Abstract

Virtual screening a collection of ~ 25,000 ChemBridge molecule collection identified two nitrogenous heterocyclic molecules, 12 and 15, with potential dual inhibitory properties against trypanosomal cruzain and rhodesain cysteine proteases. Similarity search in DrugBank found the two virtual hits with novel chemical structures with unreported anti-trypanosomal activities. Investigations into the binding mechanism by molecular dynamics simulations for 100 ns revealed the molecules were able to occupy the binding sites and stabilise the protease complexes. Binding affinities calculated using the MM/PBSA method for the last 20 ns showed that the virtual hits have comparable binding affinities to other known inhibitors from literature suggesting both molecules as promising scaffolds with dual cruzain and rhodesain inhibition properties, i.e. 12 has predicted ΔGbind values of − 38.1 and − 38.2 kcal/mol to cruzain and rhodesain, respectively, and 15 has predicted ΔGbind values of − 34.4 and − 25.8 kcal/mol to rhodesain. Per residue binding free energy decomposition studies and visual inspection at 100 ns snapshots revealed hydrogen bonding and non-polar attractions with important amino acid residues that contributed to the ΔGbind values. The interactions are similar to those previously reported in the literature. The overall ADMET predictions for the two molecules were favourable for drug development with acceptable pharmacokinetic profiles and adequate oral bioavailability.

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All data generated from this work is included in this published article and supplementary information. Any materials related to the work may be requested from the corresponding author.

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Funding

This research work is partially supported by the Chulabhorn Royal Academy research grant project code 631-CS01. This research work is supported in part by the grant from the Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science Research and Innovation. The authors would like to thank Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation for their excellent technical support.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol Univeristy, 447 Sri-Ayutthaya Road, Ratchathewi, Bangkok, 10400, Thailand

    Chatchakorn Eurtivong

  2. Program in Chemical Sciences, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6, Talat Bang Khen, Lak Si, Bangkok, 10210, Thailand

    Chatchakorn Eurtivong, Rungroj Saruengkhanphasit, Worawat Niwetmarin & Somsak Ruchirawat

  3. Center of Excellence On Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, Thailand

    Chatchakorn Eurtivong, Rungroj Saruengkhanphasit, Worawat Niwetmarin & Somsak Ruchirawat

  4. Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University, Mainz, Germany

    Collin Zimmer & Tanja Schirmeister

  5. National Omics Center, National Science and Technology Development Agency, Khlong Luang, 12120, Pathum Thani, Thailand

    Chutikarn Butkinaree

  6. Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok, 10210, Thailand

    Somsak Ruchirawat

  7. Leicester School of Allied Health Sciences, Faculty of Health and Life Sciences, de Montfort University, Leicester, UK

    Avninder S. Bhambra

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  1. Chatchakorn Eurtivong
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The experimental procedures, planning and analysis were performed by CE, CZ, TS and ASB. The manuscript draft was prepared and reviewed by CE, CB, RS, WN, TS, SR and ASB. All authors have read and approved the final manuscript.

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Correspondence to Chatchakorn Eurtivong.

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Eurtivong, C., Zimmer, C., Schirmeister, T. et al. A structure-based virtual high-throughput screening, molecular docking, molecular dynamics and MM/PBSA study identified novel putative drug-like dual inhibitors of trypanosomal cruzain and rhodesain cysteine proteases. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10600-2

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