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Identification of novel potential cathepsin-B inhibitors through pharmacophore-based virtual screening, molecular docking, and dynamics simulation studies for the treatment of Alzheimer’s disease

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Abstract

Cathepsin B is a cysteine protease lysosomal enzyme involved in several physiological functions. Overexpression of the enzyme enhances its proteolytic activity and causes the breakdown of amyloid precursor protein (APP) into neurotoxic amyloid β (Aβ), a characteristic hallmark of Alzheimer’s disease (AD). Therefore, inhibition of the enzyme is a crucial therapeutic aspect for treating the disease. Combined structure and ligand-based drug design strategies were employed in the current study to identify the novel potential cathepsin B inhibitors. Five different pharmacophore models were developed and used for the screening of the ZINC-15 database. The obtained hits were analyzed for the presence of duplicates, interfering PAINS moieties, and structural similarities based on Tanimoto’s coefficient. The molecular docking study was performed to screen hits with better target binding affinity. The top seven hits were selected and were further evaluated based on their predicted ADME properties. The resulting best hits, ZINC827855702, ZINC123282431, and ZINC95386847, were finally subjected to molecular dynamics simulation studies to determine the stability of the protein–ligand complex during the run. ZINC123282431 was obtained as the virtual lead compound for cathepsin B inhibition and may be a promising novel anti-Alzheimer agent.

Graphical abstract

The methodology utilized for the identification of novel cathepsin B inhibitors through combined structure and ligand-based drug design approach:

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Acknowledgements

JJ and RS would like to express their gratitude for the financial research assistance provided to them through teaching assistantships by the Ministry of Education (MoE), New Delhi, India. NGB is genuinely grateful to the MoE for giving him the PMRF fellowship. We gladly acclimate the resources and assistance offered by the “PARAM Shivay Facility” at the Indian Institute of Technology (BHU), Varanasi, as part of the National Supercomputing Mission, Government of India. We also wish to thank the Centre for Computing and Information Services (CCIS), Indian Institute of Technology (BHU), Varanasi, for the computational assistance.

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Authors and Affiliations

  1. Pharmaceutical Chemistry Research Laboratory–I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India

    Jatin Jangra, Nilesh Gajanan Bajad, Ravi Singh, Ashok Kumar & Sushil Kumar Singh

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  1. Jatin Jangra
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  2. Nilesh Gajanan Bajad
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  3. Ravi Singh
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  4. Ashok Kumar
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  5. Sushil Kumar Singh
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Contributions

JJ: design, conceptualization, data curation, molecular modeling and original draft preparation. NGB: computational modeling, guidance, editing and reviewing of the manuscript. RS: molecular docking. AK: supervision. SKS: supervision, reviewing, administering, and editing of the manuscript.

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Correspondence to Sushil Kumar Singh.

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Jangra, J., Bajad, N.G., Singh, R. et al. Identification of novel potential cathepsin-B inhibitors through pharmacophore-based virtual screening, molecular docking, and dynamics simulation studies for the treatment of Alzheimer’s disease. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10821-z

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