Identification of novel cathepsin B inhibitors with implications in Alzheimer’s disease: computational refining and biochemical evaluation

Nitin Chitranshi, Ashutosh Kumar, Samran Sheriff, Veer Gupta, Angela Godinez, Danit Saks, Soumalya Sarkar, Ting Shen, Mehdi Mirzaei, Devaraj Basavarajappa, Morteza Abyadeh, Sachin K. Singh, Kamal Dua, Kam Y. J. Zhang, Stuart L. Graham, Vivek Gupta

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
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Amyloid precursor protein (APP), upon proteolytic degradation, forms aggregates of amyloid β (Aβ) and plaques in the brain, which are pathological hallmarks of Alzheimer’s disease (AD). Cathepsin B is a cysteine protease enzyme that catalyzes the proteolytic degradation of APP in the brain. Thus, cathepsin B inhibition is a crucial therapeutic aspect for the discovery of new anti-Alzheimer’s drugs. In this study, we have employed mixed-feature ligand-based virtual screening (LBVS) by integrating pharmacophore mapping, docking, and molecular dynamics to detect small, potent molecules that act as cathepsin B inhibitors. The LBVS model was generated by using hydrophobic (HY), hydrogen bond acceptor (HBA), and hydrogen bond donor (HBD) features, using a dataset of 24 known cathepsin B inhibitors of both natural and synthetic origins. A validated eight-feature pharmacophore hypothesis (Hypo III) was utilized to screen the Maybridge chemical database. The docking score, MM-PBSA, and MM-GBSA methodology was applied to prioritize the lead compounds as virtual screening hits. These compounds share a common amide scaffold, and showed important interactions with Gln23, Cys29, His110, His111, Glu122, His199, and Trp221. The identified inhibitors were further evaluated for cathepsin-B-inhibitory activity. Our study suggests that pyridine, acetamide, and benzohydrazide compounds could be used as a starting point for the development of novel therapeutics.
Original languageEnglish
Article number1946
Pages (from-to)1-30
Number of pages30
Issue number8
Publication statusPublished - 31 Jul 2021

Bibliographical note

Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


  • Alzheimer’s disease
  • cathepsin B
  • 3D pharmacophore
  • virtual screening
  • docking
  • molecular dynamics


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