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Comparative analysis of compound NSC13728 as Omomyc homodimer stabilizer by molecular dynamics simulation and MM/GBSA free energy calculation

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Abstract

Myc is a master transcriptional regulator that controls almost all cellular processes, whose function is dependent on dimerization with its obligate partner Max. Stabilization of Max homodimer by small molecules (such as compound NSC13728) has proven an effective way to reduce the availability of Myc-Max dimer. Omomyc, a peptide inhibitor of Myc, is able to form Omomyc homodimer, which can competitively inhibit the binding of Myc-Max to the E-box of DNA. Considering the high amino acid sequence homology between Omomyc and Max, we put forward the hypothesis that Max-Max stabilizers could stabilize the Omomyc homodimer. Hence, through molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation, we discovered that the stability of Omomyc-Omomyc is remarkably higher than that of Max-Max. Moreover, after adding the compound NSC13728 into the well-defined “Site 3,” the binding affinity between two Omomyc monomers can be further increased. Compound NSC13728 has stronger binding interaction to Omomyc-Omomyc than to Max-Max. “Site 3” of Omomyc is more hydrophobic than that of Max, which enlightens us that the more potent Omomyc-Omomyc stabilizers may be hydrophobic in structure.

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Funding

This work was supported by the Natural Science Foundation of Jiangsu Province (grant number BK20201157), the Six Talent Peaks Project in Jiangsu Province (grant number YY-046), and the Qinglan Project of Jiangsu Province of China.

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  1. Jian Gao and Yinchuan Wang contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221,004, PR, China

    Jian Gao, Yinchuan Wang, Kaihang Li, Jinyuan Zhang & Xiaoju Geng

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  1. Jian Gao
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Contributions

Jian Gao, Yinchuan Wang, Kaihang Li, and Jinyuan Zhang performed the molecular dynamics simulations; Xiaoju Geng and Jinyuan Zhang performed the MM/GBSA binding free energy calculations; Jian Gao, Yinchuan Wang, Kaihang Li, and Jinyuan Zhang analyzed the data and wrote the paper.

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Correspondence to Jian Gao.

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Gao, J., Wang, Y., Li, K. et al. Comparative analysis of compound NSC13728 as Omomyc homodimer stabilizer by molecular dynamics simulation and MM/GBSA free energy calculation. J Mol Model 28, 92 (2022). https://doi.org/10.1007/s00894-022-05082-2

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