Tyrosine-based asymmetric urea ligand for prostate carcinoma: Tuning biological efficacy through in silico studies.

Affiliation

Discipline of Chemistry, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore 453 552, India; Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore 453 552, India. Electronic address: [Email]

Abstract

In this article, we have explored the chemical interactions of tyrosine-based asymmetric urea ligands in the binding pockets of prostate specific membrane antigen (PSMA) through in silico studies. The S1 pocket of the PSMA protein offers better scope for modifications in the urea ligands to improve the binding affinity. Accordingly, tyrosine-based (S)-2-(3-((S)-1-carboxy-2-(4-(carboxymethoxy)phenyl)ethyl)ureido)pentanedioic acid (CYUE, 3) ligand was designed, synthesized and predicted to possess inhibition constant (Ki) of 55 nM with PSMA protein. The CYUE (3) ligand was further elaborated into a fluorescent diagnostic probe for detection of PSMA+ cancers. In vitro studies on human malignant cell lines such as LNCaP and PC-3 were performed to show the efficacy and specificity of the newly synthesized bio-construct. The fluorescent bio-conjugate was found to be very specific to the PSMA protein with an overall binding affinity constant (KD) of 88 nM.

Keywords

Diagnostic probe,In silico,In vitro study,PSMA,Tyrosine-based urea ligands,

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