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

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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 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.

The common active site residues involved in interaction with ligands

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Acknowledgments

SSJ is thankful for VIPER principal and CSIR-IICT Hyderabad for providing infrastructure facility.

Funding

This study is supported by the Science and Engineering Research Board (SERB) providing postdoctoral funding project (PDF/2017/001556).

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Authors and Affiliations

  1. CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad, 500007, India

    Surender Singh Jadav

  2. Center for Molecular Cancer Research (CMCR), Vishnu Institute of Pharmaceutical Education and Research (VIPER), Narsapur, Medak, 502313, India

    Surender Singh Jadav & Ramesh Alluri

  3. Chemistry Department, De La Salle University, 2401 Taft Avenue, 0992, Manila, Philippines

    Stephani Joy Y. Macalino

Authors
  1. Surender Singh Jadav
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  2. Stephani Joy Y. Macalino
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  3. Ramesh Alluri
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Correspondence to Surender Singh Jadav.

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Highlights

• Colorectal cancer is second leading cause of cancer death worldwide

• APC-Asef complex causes cancer cell migration in the intestine

• SBVS and MD simulations yielded 16 small molecules as APC-Asefinhibitors

• Ligand amide bonds are required for effective binding

• Arg549 can act as an amide bond detector to open the binding site

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Jadav, S.S., Macalino, S.J.Y. & Alluri, R. Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations. J Mol Model 26, 207 (2020). https://doi.org/10.1007/s00894-020-04467-5

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  • DOI: https://doi.org/10.1007/s00894-020-04467-5

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