Here, we describe the mechanism of diphenyl α-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 dose-response 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·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.