title: In silico screening and biological evaluation of inhibitors of Src-SH3 domain interaction with a proline-rich ligand.
abstract: Src signalling and transduction are directly involved in cell growth, cell cycle, malignant transformation and cell migration, providing therapeutic opportunities through inhibition of Src. Here we report virtual screening for novel compounds that inhibit the Src-SH3 protein-protein interaction with a proline-rich peptide ligand. Computational docking of the ZINC compound database was performed using GOLD. Top-scoring compounds were assayed using a fluorescence polarization-based assay. A benzoquinoline derivative showed micromolar inhibition of binding between Src-SH3 and the proline-rich peptide. Several analogues were subsequently assayed showing the requirement of a linker between the benzoquinoline and phenyl rings, and electron donating substituents on the phenyl ring.
authors: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PT, UK.
authors: Noor
authors: N
authors: Atatreh
authors: Cvetan
authors: C
authors: Stojkoski
authors: Phillippa
authors: P
authors: Smith
authors: Grant W
authors: GW
authors: Booker
authors: Caroline
authors: C
authors: Dive
authors: A David
authors: AD
authors: Frenkel
authors: Sally
authors: S
authors: Freeman
authors: Richard A
authors: RA
authors: Bryce
mesh_terms: D000595:Amino Acid Sequence; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D008958:Models, Molecular; D011392:Proline / Q000737:chemistry*; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D011804:Quinolines; D011392:Proline; D016392:Proto-Oncogene Proteins pp60(c-src)