Journal article
Structure-Based Drug Design of Diphenyl alpha-Aminoalkylphosphonates as Prostate-Specific Antigen Antagonists
Journal of chemical information and modeling, v 54(10), pp 2967-2979
01 Oct 2014
PMID: 25186464
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Here, we describe the mechanism of diphenyl alpha-aminoalkylphosphonate ester derivatives as potent inhibitors of prostate-specific antigen (PSA), a likely protease responsible for the advancement of prostate tumor progression. The AutoDock 4.2 molecular docking suite was utilized to model covalent and noncovalent binding of this class of inhibitors to predict crystallographic poses and compare experimental IC50 doseresponse curves and in silico potencies for providing future more specific rational drug design. The new lead compound R/S-diphenyl[N-benzyloxycarbonylamino(4-carbamoylphenyl)methyl]phosphonate is being reported in this study as a potent inhibitor of PSA activity (IC50 = 250 nM; AutoDock Score = -8.29/9.14 kJ center dot mol(1) for R/S). Molecular dynamics (MD) simulations using GROMACS 4.6.5 was used to obtain trajectories of the top ligand and validate key interactions in the binding complex. A hydrogen-bonding map was used to confirm interactions between the lead compound and residues THR190, SER217, and SER227 in the P1 pocket. The modeling study introduces novel aminoalkylphosphonates as a potential drug candidate for targeting PSA by optimizing P1 binding affinities.
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Details
- Title
- Structure-Based Drug Design of Diphenyl alpha-Aminoalkylphosphonates as Prostate-Specific Antigen Antagonists
- Creators
- Arben Kojtari - Drexel UniversityVishal Shah - Drexel UniversityJacob S. Babinec - Drexel UniversityCatherine Yang - Rowan UniversityHai-Feng Ji - Drexel University
- Publication Details
- Journal of chemical information and modeling, v 54(10), pp 2967-2979
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 13
- Grant note
- R15CA089162 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 1R15CA089162-01 / NCI of National Institutes of Health, NCI-NIH
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:000343849600030
- Scopus ID
- 2-s2.0-84908224805
- Other Identifier
- 991019330626304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Multidisciplinary
- Computer Science, Information Systems
- Computer Science, Interdisciplinary Applications