Design, identification, and validation of novel C-terminal binding protein modulators

Abstract

C-terminal binding proteins (CtBP) are a prospective therapeutic target in a number of cancers. These proteins are oncogenic transcriptional co-regulators that can decrease cell migration, eliminate cellular invasion, and enhance DNA repair, if they are inhibited. The aim of the study is to identify high affinity CtBP modulators with a propensity to in vivo bioavailability, using the experimental molecules 4-methylthio 2-oxobutyric acid (MTOB) and hydroxyimino-3-phenylpropanoic acid (HIPP), as the lead molecules. During virtual screening, MTOB and HIPP pharmacophores were modelled and the consensus pharmacophore was created by superimposition of the two pharmacophores. Hits were identified and drug- and lead-like filters were applied. A protomol was modelled and the hits were docked into it and ranked in order of affinity to the protomol, in order to identify the highest affinity lead-like molecule. Through virtual screening, 674 Lipinski rule compliant hit structures were acquired. 2D topology maps were then generated to guide seed structure modelling during the de novo design process where two successful seeds were created. The molecules generated by the seeds were categorized into pharmacophorically similar families in order of ligand binding affinity and then filtered according to Lipinski’s rules. The 5 optimal molecules with regards to their log P and binding affinity were then assessed for toxicity. In conclusion, CtBP in isoform 1 and 2, has a role in future cancer therapy. The structural approaches used helped in the development of novel antineoplastic CtBP inhibitors because the leads used were viable.