Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations

Journal of Molecular Modeling
Surender Singh JadavRamesh Alluri

Abstract

Colorectal cancer, which is considered one of the leading causes of mortality worldwide, develops through the formation of benign polyps on the inner colon or rectum wall. Truncations in adenomatous polyposis coli (APC) gene lead to the spread of the disease in the entire colon region when combined with the guanine nucleotide exchange factor (GEF) Asef. A series of peptidomimetic agents were previously discovered as protein-protein interaction inhibitors that can target the APC-Asef interface. Structure-based virtual screening (SBVS), using a set of docking methods combined with molecular dynamics simulations, was carried out to identify new small drug-like agents. After the initial screening process, compounds with diverse chemical scaffolds and direct interaction with Arg549 and other active site residues were chosen and subjected to induce fit. The amide functional group found in the ligand hit structures showed strong interactions with Arg549, leading to observable conformational changes that allow suitable positioning within the peptide binding site. Furthermore, the pH-specific MD simulations of the top hit 838 within the APC-Asef binding site depicted significant interactions required for biochemical recognition in chang...Continue Reading

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Citations

Jan 15, 2021·European Journal of Medicinal Chemistry·Manjinder Singh PhullPrathama S Mainkar
May 11, 2021·Frontiers in Molecular Biosciences·Xiuyan YangShaoyong Lu

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