Interactions of Urea-Based Inhibitors with Prostate-Specific Membrane Antigen for Boron Neutron Capture Therapy

Abstract

In this study, molecular interactions of prostate-specific membrane antigen (PSMA) with five chemically distinct urea-based boron-containing inhibitors have been investigated at the atomic level using molecular docking and molecular dynamics simulations. The PSMA–inhibitor complexations have been analyzed by comparing their binding modes, secondary structures, root-mean-square deviations, noncovalent interactions, principal components, and binding free energies. PSMA is a cell surface glycoprotein upregulated in cancerous cells and can be targeted by boron-labeled inhibitors for boron neutron capture therapy (BNCT). The effective BNCT requires the selective boron delivery to the tumor area and highly specific PSMA-mediated cellular uptake by tumor. Thus, a potent inhibitor must exhibit both high binding affinity and high boron density. The computational results suggest that the chemical nature of inhibitors affects the binding mode and their association with PSMA is primarily dominated by hydrogen bonding, salt bridge, electrostatic, and π–π interactions. The binding free energies (−28.0, −15.2, −43.9, −23.2, and −38.2 kcal/mol) calculated using λ-dynamics for all inhibitors ( In1–5 ) predict preferential binding that is in accordance with experimental data. Among all inhibitors, In5 was found to be the best candidate for BNCT. The binding of this inhibitor to PSMA preserved its overall secondary structure. These results provide computational insights into the coordination flexibility of PSMA and its interaction with various inhibitors. They can be used for the design and synthesis of efficient BNCT agents with improved drug selectivity and high boron percentage.

Synthesis and Preclinical Evaluation of PSMA-Targeted 111In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

“…Nevertheless, the metal complexation and the presence of the Gly-Gly-Gly linker showed some influence on the binding affinity of the compounds. To better understand these effects, in silico approaches based on molecular docking and molecular dynamics simulations are a good option, as previously reported by other authors for different families of PSMA inhibitors, 39,50,51 taking advantage of the availability of the X-ray structure of the PSMA protein. 52 However, these in silico studies were outside the scope of the present work.…”

Targeting the organelle for radiosensitization in cancer radiotherapy

“…Notably, the membrane proteins, like Hsp70 [229] , could determine the radiosensitizing effect of cancer cells. Furthermore, Hu et al analyzed boron- containing inhibitors targeting the upregulated prostate-specific membrane antigen (PSMA), a cell surface glycoprotein overexpressed in cancerous cells, for BNCT [230] . Similarly, the efficacy of boron-containing PSMA inhibitors has also been demonstrated, highlighting their potential utility in BNCT [231] .…”

CIB2 as a Ca2+Sensor for Auditory Mechano-Electrical Transduction and Linked to Genetic-Heterogeneity ofTMC1in Hearing Loss

“…Subsequently, energy minimization, NVT, and NPT equilibrations were conducted sequentially to stabilize the temperature and pressure of the system to 310 K and 1 bar, respectively. Finally, MD simulation was performed on the equilibrated structure for 300 ns under the NPT ensemble as in previous reports 62,63 . To simulate the apo state (Fig.…”