Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Chitranshi, N; Kumar, A; Sheriff, S; Gupta, V; Godinez, A; Saks, D; Sarkar, S; Shen, T; Mirzaei, M; Basavarajappa, D; Abyadeh, M; Singh, SK; Dua, K; Zhang, KYJ; Graham, SL; Gupta, V

Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Chitranshi, N Kumar, A Sheriff, S Gupta, V Godinez, A Saks, D Sarkar, S Shen, T Mirzaei, M Basavarajappa, D Abyadeh, M Singh, SK Dua, K

Zhang, KYJ Graham, SL Gupta, V

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Publisher:: MDPI AG
Publication Type:: Journal Article
Citation:: Cells, 10, (8), pp. 1946-1946

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Field	Value	Language
dc.contributor.author	Chitranshi, N
dc.contributor.author	Kumar, A
dc.contributor.author	Sheriff, S
dc.contributor.author	Gupta, V
dc.contributor.author	Godinez, A
dc.contributor.author	Saks, D
dc.contributor.author	Sarkar, S
dc.contributor.author	Shen, T
dc.contributor.author	Mirzaei, M
dc.contributor.author	Basavarajappa, D
dc.contributor.author	Abyadeh, M
dc.contributor.author	Singh, SK
dc.contributor.author	Dua, K https://orcid.org/0000-0002-7507-1159
dc.contributor.author	Zhang, KYJ
dc.contributor.author	Graham, SL
dc.contributor.author	Gupta, V
dc.date.accessioned	2021-08-04T07:02:53Z
dc.date.available	2021-08-04T07:02:53Z
dc.identifier.citation	Cells, 10, (8), pp. 1946-1946
dc.identifier.issn	2073-4409
dc.identifier.uri	http://hdl.handle.net/10453/150036
dc.description.abstract	<jats:p>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.</jats:p>
dc.language	en
dc.publisher	MDPI AG
dc.relation.ispartof	Cells
dc.relation.isbasedon	10.3390/cells10081946
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	Copyright: © 2021 by the authors. Li-censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con-ditions of the Creative Commons At-tribution (CC BY) license (http://crea-tivecommons.org/licenses/by/4.0/)
dc.title	Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation
dc.type	Journal Article
utslib.citation.volume	10
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health/GSH.Pharmacy
utslib.copyright.status	open_access	*
dc.date.updated	2021-08-04T07:02:50Z
pubs.issue	8
pubs.publication-status	Published online
pubs.volume	10
utslib.citation.issue	8

Abstract:

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.

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http://hdl.handle.net/10453/150036