Structure-based design & synthesis of [alpha]-aminoalkylphosphonate esters for prostate-specific antigen inhibition

Rational ligand design of diphenyl α-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.Ph.D., Chemistry -- Drexel University, 201

Metal Organic Framework Micro/Nanopillars of Cu(BTC)·3H2O and Zn(ADC)·DMSO

In this work, we report the optical and thermal properties of Cu(BTC)·3H2O (BTC = 1,3,5-benzenetricarboxylic acid) and Zn(ADC)·DMSO (ADC = 9,10- anthracenedicarboxylic acid, DMSO = dimethyl sulfoxide) metal-organic frameworks (MOFs) micro/nanopillars. The morphologies of MOFs on surfaces are most in the form of micro/nanopillars that were vertically oriented on the surface. The size and morphology of the pillars depend on the evaporation time, concentration, solvent, substrate, and starting volume of solutions. The crystal structures of the nanopillars and micropillars are the same, confirmed by powder XRD. Zn(ADC)·DMSO pillars have a strong blue fluorescence. Most of ADC in the pillars are in the form of monomers, which is different from ADC in the solid powder

Self-Assembled Microwires of Terephthalic Acid and Melamine

Self-assembled microwires of terephthalic acid (TPA) and melamine are prepared through the evaporation of water in a solution mixture of TPA and melamine. The microwires were characterized by using scanning electron microscope (SEM), attenuated total reflection infrared (ATR-IR) spectra, and cross-polarized optical microscopy (CPOM). The TPA•M microwires showed semi-conductive properties