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Summer Research Fellowship Programme of India's Science Academies

In silico studies of various C-terminal Binding Protein-1 inhibitors

Nivethithan M

2nd year Undergraduate, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India

Dr. Madhu Chopra

Laboratory of Molecular Modeling and Drug Design, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110 007, India.

Abstract

C-terminal Binding Proteins (CtBPs), which were first identified by their interaction with E1A oncogene of Adenovirus, have found to be promising anti-cancer targets. C-terminal Binding Protein 1 (CtBP1) acts as a transcriptional corepressor. CtBP1 overexpression is known to be pro-tumorigenic and affects the regulation of gene networks associated with hallmarks of cancer such as epithelial-mesenchymal transition, proliferation, migration, invasion, and apoptosis evasion. Unlike other proteins in D-2-hydroxyacid dehydrogenase family, Tryptophan (Trp318) binding site and the hydrophilic cavity are present in this proteins’ catalytic domain. A water network threads through the cavity, providing hydrogen bond linkage between the substrates and an NAD. Even though a number of ligands, although limited, are reported including 4-(methylsulfanyl)-2-oxobutanoic acid (MTOB), phenyl pyruvate (PPy), (2E)-2-(hydroxyimino)-3-phenylpropanoic acid (HIPP) and its derivatives, the structural and functional features affect the search for new inhibitors. These inhibitors bind to the active site and prevents CtBP1 oligomerization. MTOB bound structure consists of four water molecules (W1-4) in the cavity with W1 and W4 interacting with MTOB and NADP respectively. In HIPP, W1 is displaced by its oxime group. W1 is displaced by non-canonical PPy in the PPy bound structure. HIPP effectively displaces two water molecules and only W4 is unperturbed. In PPy bound structure, W2 and W3 are completely displaced due to interaction of novel A123 residue. Here, a detailed procedure for Molecular Docking studies of various inhibitors of CtBP1 by using one of its crystal structures considering the presence of water molecules is discussed. In silico methods such as Pharmacophore development were used to find effective inhibitors by using the existing knowledge of the protein's binding region, ligands' structure, IC50 values and the docking studies conducted.

Keywords: inhibitor design, pharmacophore development, 2-hydroxyacid dehydrogenases, molecular docking, 2-(hydroxyimino)-3-phenylpropanoic acid, anti-cancer targets

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