Structure-guided virtual screening reveals phytoconstituents as potent cathepsin B inhibitors: Implications for cancer, traumatic brain injury, and Alzheimer’s disease
Cathepsin B (CathB) is a lysosomal cysteine protease involved in various pathological and physiological processes and is becoming an attractive target for drug intervention in complex diseases like cancer, traumatic brain injury (TBI) and Alzheimer’s disease (AD). The aberrant expression of CathB dr...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2025.1581711/full |
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| author | Nageeb Hassan Mohammad Furkan Mohd Shahnawaz Khan Azna Zuberi Moyad Shahwan Moyad Shahwan Anas Shamsi |
| author_facet | Nageeb Hassan Mohammad Furkan Mohd Shahnawaz Khan Azna Zuberi Moyad Shahwan Moyad Shahwan Anas Shamsi |
| author_sort | Nageeb Hassan |
| collection | DOAJ |
| description | Cathepsin B (CathB) is a lysosomal cysteine protease involved in various pathological and physiological processes and is becoming an attractive target for drug intervention in complex diseases like cancer, traumatic brain injury (TBI) and Alzheimer’s disease (AD). The aberrant expression of CathB drives tumor invasiveness and metastasis and exacerbates neurodegeneration and behavioral deficits in AD and TBI. However, current CathB inhibitors lack clinical translation due to poor selectivity, bioavailability, or toxicity, necessitating novel therapeutic candidates. To address this gap, an in silico screening was conducted through the structure-guided virtual screening with the IMPPAT 2 phytochemical library for potential CathB inhibitors. Using the control inhibitor CA-074Me as a benchmark, two phytoconstituents, Nicandrenone and Picrasidine M, emerged with superior binding affinities, ligand efficiency, and robust interactions with the active site residues of CathB. These molecules were further validated through molecular dynamics (MD) simulations, which supported their ability to bind stably to the CathB active pocket and thus likely hold their durable inhibitory activity. Remarkably, these phytoconstituents exhibited favorable pharmacokinetic and ADMET profiles, which validate their potential as lead compounds. The current study showed that these bioactive compounds could be developed as new CathB inhibitors, opening a new frontier for their use in the management of such diseases as cancer, TBI, and AD. |
| format | Article |
| id | doaj-art-ebdf511ae1674cf2b0ad8cb3c3e4b741 |
| institution | OA Journals |
| issn | 2296-889X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj-art-ebdf511ae1674cf2b0ad8cb3c3e4b7412025-08-20T02:11:57ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2025-04-011210.3389/fmolb.2025.15817111581711Structure-guided virtual screening reveals phytoconstituents as potent cathepsin B inhibitors: Implications for cancer, traumatic brain injury, and Alzheimer’s diseaseNageeb Hassan0Mohammad Furkan1Mohd Shahnawaz Khan2Azna Zuberi3Moyad Shahwan4Moyad Shahwan5Anas Shamsi6Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab EmiratesDepartment of Biochemistry, Aligarh Muslim University, Aligarh, IndiaDepartment of Biochemistry, King Saud University, Riyadh, Saudi ArabiaDivision of Reproductive Science in Medicine, Department of Obstetrics & Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab EmiratesCenter for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab EmiratesCenter for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab EmiratesCathepsin B (CathB) is a lysosomal cysteine protease involved in various pathological and physiological processes and is becoming an attractive target for drug intervention in complex diseases like cancer, traumatic brain injury (TBI) and Alzheimer’s disease (AD). The aberrant expression of CathB drives tumor invasiveness and metastasis and exacerbates neurodegeneration and behavioral deficits in AD and TBI. However, current CathB inhibitors lack clinical translation due to poor selectivity, bioavailability, or toxicity, necessitating novel therapeutic candidates. To address this gap, an in silico screening was conducted through the structure-guided virtual screening with the IMPPAT 2 phytochemical library for potential CathB inhibitors. Using the control inhibitor CA-074Me as a benchmark, two phytoconstituents, Nicandrenone and Picrasidine M, emerged with superior binding affinities, ligand efficiency, and robust interactions with the active site residues of CathB. These molecules were further validated through molecular dynamics (MD) simulations, which supported their ability to bind stably to the CathB active pocket and thus likely hold their durable inhibitory activity. Remarkably, these phytoconstituents exhibited favorable pharmacokinetic and ADMET profiles, which validate their potential as lead compounds. The current study showed that these bioactive compounds could be developed as new CathB inhibitors, opening a new frontier for their use in the management of such diseases as cancer, TBI, and AD.https://www.frontiersin.org/articles/10.3389/fmolb.2025.1581711/fullcathepsin Bcancertraumatic brain injuryAlzheimer’s diseasedrug discoveryvirtual screening hERG blocker hepatotoxicity |
| spellingShingle | Nageeb Hassan Mohammad Furkan Mohd Shahnawaz Khan Azna Zuberi Moyad Shahwan Moyad Shahwan Anas Shamsi Structure-guided virtual screening reveals phytoconstituents as potent cathepsin B inhibitors: Implications for cancer, traumatic brain injury, and Alzheimer’s disease Frontiers in Molecular Biosciences cathepsin B cancer traumatic brain injury Alzheimer’s disease drug discovery virtual screening hERG blocker hepatotoxicity |
| title | Structure-guided virtual screening reveals phytoconstituents as potent cathepsin B inhibitors: Implications for cancer, traumatic brain injury, and Alzheimer’s disease |
| title_full | Structure-guided virtual screening reveals phytoconstituents as potent cathepsin B inhibitors: Implications for cancer, traumatic brain injury, and Alzheimer’s disease |
| title_fullStr | Structure-guided virtual screening reveals phytoconstituents as potent cathepsin B inhibitors: Implications for cancer, traumatic brain injury, and Alzheimer’s disease |
| title_full_unstemmed | Structure-guided virtual screening reveals phytoconstituents as potent cathepsin B inhibitors: Implications for cancer, traumatic brain injury, and Alzheimer’s disease |
| title_short | Structure-guided virtual screening reveals phytoconstituents as potent cathepsin B inhibitors: Implications for cancer, traumatic brain injury, and Alzheimer’s disease |
| title_sort | structure guided virtual screening reveals phytoconstituents as potent cathepsin b inhibitors implications for cancer traumatic brain injury and alzheimer s disease |
| topic | cathepsin B cancer traumatic brain injury Alzheimer’s disease drug discovery virtual screening hERG blocker hepatotoxicity |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2025.1581711/full |
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