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The identification of c-Abl inhibitors as potential agents for Parkinson’s disease: a preliminary in silico approach

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Abstract

Parkinson’s disease (PD) is the most common movement disorder worldwide. PD is primarily associated with the mutation, overexpression, and phosphorylation of α-synuclein. At the molecular level, the upstream protein c-Abl, a tyrosine kinase, has been shown to regulate α-synuclein activation and expression patterns. This study aimed to identify potential c-Abl inhibitors through in silico approaches. Molecular docking was performed using PyRx software, followed by Prime MM-GBSA studies. BBB permeability and toxicity were predicted using CBligand and ProTox-II, respectively. ADME was assessed using QikProp. Molecular dynamics were carried out using Desmond (Academic version). DFT calculations were performed using the Gaussian 16 suite program. The binding scores of the top hits, norimatinib, DB07326, and entinostat were − 11.8 kcal/mol, − 11.8 kcal/mol, and − 10.8 kcal/mol, respectively. These hits displayed drug-likeness with acceptable ADME properties, except for the standard, nilotinib, which violated Lipinski’s rule of five. Similarly, the molecular dynamics showed that the top hits remained stable during the 100 ns simulation. DFT results indicate DB04739 as a potent reactive hit. While based on toxicity prediction, entinostat may be a potential candidate for preclinical and clinical testing in PD. Further studies are warranted to confirm the activity and efficacy of these ligands for PD.

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Acknowledgements

The author would like to thank the Department of Science and Technology—Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST-FIST), New Delhi for their infrastructure support to our department. The author would also like to express a special thanks to the management of JSS College of Pharmacy, Ooty and JSS Academy of Higher Education & Research, Mysuru.

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The study did not receive any funding for carrying out the work.

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  1. Emdormi Rymbai and Dhritiman Roy have contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India

    Emdormi Rymbai

  2. Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India

    Dhritiman Roy

  3. Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India

    Srikanth Jupudi

  4. Department of Sciences and Humanities, Vignan’s Foundation for Science, Technology and Research (Deemed to be University), Vadlamudi, Guntur, Andhra Pradesh, India

    Venkatesan Srinivasadesikan

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Contributions

ER performed the literature review, designed the concept, performed the study, and interpretation of results. DR performed the study, interpretation of results, and edited the manuscript. SJ and VS performed and interpreted the DFT studies. All the authors approved the final manuscript for submission and publication.

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Correspondence to Emdormi Rymbai.

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Rymbai, E., Roy, D., Jupudi, S. et al. The identification of c-Abl inhibitors as potential agents for Parkinson’s disease: a preliminary in silico approach. Mol Divers (2024). https://doi.org/10.1007/s11030-023-10796-3

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