Cited by 6Computational Drug Discovery MethodsProtein Structure and DynamicsProtein Interaction Studies and Fluorescence Analysis

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

Gao, Jian, Wang, Yinchuan, Li, Kaihang, Zhang, Jinyuan, Geng, Xiaoju·2022·Journal of Molecular Modeling

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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Crossref · 10.1007/s00894-022-05082-2

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Authors
Gao, J., Wang, Y., Li, K., Zhang, J., & Geng, X.
Affiliations
Xuzhou Medical College (CN)
Corresponding author
Gao, Jian
Venue
Journal of Molecular Modeling
Published
2022-03-16
Volume
28
Issue
4
Pages
92-92
ISSN
  • 0948-5023 (ISSN-L)
  • 1610-2940
OpenAlex
W4220817194
Cited by
6
References
31
Citations by year
2025: 1 · 2024: 2 · 2023: 2 · 2022: 1
FWCI
0.81
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Molecular Modeling (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Natural Science Foundation of Jiangsu Province (BK20201157)
  • Six Talent Peaks Project in Jiangsu Province (YY-046)
  • Qinglan Project of Jiangsu Province of China (Jian Gao)
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Keywords
Omomyc, Max, peptide inhibitors, E-box DNA binding, hydrophobic binding site, small-molecule binding affinity, transcriptional regulation
MeSH terms
DNA, Protein Binding, Proto-Oncogene Proteins c-myc, Dimerization, Molecular Dynamics Simulation

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