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Dissertation
Structure-based design & synthesis of [alpha]-aminoalkylphosphonate esters for prostate-specific antigen inhibition
Doctor of Philosophy (Ph.D.), Drexel University
01 Dec 2014
DOI:
https://doi.org/10.17918/etd-6359
Abstract
Rational ligand design of diphenyl [alpha]-aminoalkylphosphonate ester derivatives were studied as inhibitors of prostate-specific antigen (PSA), a serine protease implicated in the advancement of prostate tumor progression. AutoDock 4.2 molecular docking suite was utilized to model covalent and non-covalent binding of this class of inhibitors to predict crystallographic poses and compare experimental IC50 concentration-dependent reponse curves and in silico potencies. The docking method utilized challenges the status quo for docking covalently-binding ligands and can be used to formulate a more robust structure-activity relationship. The new lead compound R/S-diphenyl[N-benzyloxycarbonylamino(4-carbamoylphenyl)methyl]phosphonate was identified using this structure-based approach. Additionally, tripeptide derivatives of the aforementioned lead were modeled using a similar approach. An incremental build method was utilized to improve computational efficiency of peptide docking. Peptidomimetic compounds were chosen from the compiled virtual screen and were synthesized using a convergent synthetic scheme. Molecular dynamics (MD) simulations using GROMACS 4.6.5 were used to obtain trajectories of selected ligands and validate key interactions in the binding complexes. A hydrogen-bonding map was used to confirm interactions between the lead compound and residues THR190, SER217, and SER227 in the binding pocket. Additionally, the importance of the classic kallikrein loop (CKL) and its interaction with the extended substrate were highlighted in the MD analysis. Ligand- and structure-based approaches were compared using QSAR models derived using 2D ligand descriptors and docking energies. This modeling study introduces novel aminoalkylphosphonates as potential drug candidates for targeting PSA for prostate cancer treatment.
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Details
- Title
- Structure-based design & synthesis of [alpha]-aminoalkylphosphonate esters for prostate-specific antigen inhibition
- Creators
- Arben Kojtari - DU
- Contributors
- Haifeng Ji (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Arts and Sciences; Chemistry; Drexel University
- Other Identifier
- 6359; 991014632320904721