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

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...

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Main Authors: Jadav, Surender Singh, Macalino, Stephani Joy Y., Alluri, Ramesh
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Published: Animo Repository 2020
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Online Access:https://animorepository.dlsu.edu.ph/faculty_research/1399
https://animorepository.dlsu.edu.ph/context/faculty_research/article/2398/type/native/viewcontent/s00894_020_04467_5.html
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spelling oai:animorepository.dlsu.edu.ph:faculty_research-23982024-01-16T06:40:32Z Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations Jadav, Surender Singh Macalino, Stephani Joy Y. Alluri, Ramesh 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 changing microenvironment. Predicted inhibitory constant (Ki) values and binding free energies of hits further described the significance of the amide group over the other chemical scaffolds. This combination of in silico approaches provides key insights for colorectal drug discovery programs targeting the APC-Asef interaction. 2020-08-01T07:00:00Z text text/html https://animorepository.dlsu.edu.ph/faculty_research/1399 info:doi/10.1007/s00894-020-04467-5 https://animorepository.dlsu.edu.ph/context/faculty_research/article/2398/type/native/viewcontent/s00894_020_04467_5.html Faculty Research Work Animo Repository Colon (Anatomy)—Cancer Polyps (Pathology) Medical screening—Simulation methods Chemistry
institution De La Salle University
building De La Salle University Library
continent Asia
country Philippines
Philippines
content_provider De La Salle University Library
collection DLSU Institutional Repository
topic Colon (Anatomy)—Cancer
Polyps (Pathology)
Medical screening—Simulation methods
Chemistry
spellingShingle Colon (Anatomy)—Cancer
Polyps (Pathology)
Medical screening—Simulation methods
Chemistry
Jadav, Surender Singh
Macalino, Stephani Joy Y.
Alluri, Ramesh
Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations
description 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 changing microenvironment. Predicted inhibitory constant (Ki) values and binding free energies of hits further described the significance of the amide group over the other chemical scaffolds. This combination of in silico approaches provides key insights for colorectal drug discovery programs targeting the APC-Asef interaction.
format text
author Jadav, Surender Singh
Macalino, Stephani Joy Y.
Alluri, Ramesh
author_facet Jadav, Surender Singh
Macalino, Stephani Joy Y.
Alluri, Ramesh
author_sort Jadav, Surender Singh
title Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations
title_short Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations
title_full Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations
title_fullStr Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations
title_full_unstemmed Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations
title_sort structure-based discovery of small molecule apc-asef interaction inhibitors: in silico approaches and molecular dynamics simulations
publisher Animo Repository
publishDate 2020
url https://animorepository.dlsu.edu.ph/faculty_research/1399
https://animorepository.dlsu.edu.ph/context/faculty_research/article/2398/type/native/viewcontent/s00894_020_04467_5.html
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