Study of SHMT2 Inhibitors and Their Binding Mechanism by Computational Alanine Scanning

Liping He, Jingxiao Bao, Yunpeng Yang, Suzhen Dong, Lujia Zhang, Yifei Qi, John Zhang

Research output: Contribution to journalArticle

Abstract

Mitochondrial serine hydroxymethyl transferase isoform 2 (SHMT2) has attracted increasing attention as a pivotal catalyzing regulator of the serine/glycine pathway in the one-carbon metabolism of cancer cells. However, few inhibitors that target this potential anticancer target have been discovered. Quantitative characterization of the interactions between SHMT2 and its known inhibitors should benefit future discovery of novel inhibitors. In this study, we employed a recently developed alanine-scanning-interaction-entropy method to quantitatively calculate the residue-specific binding free energy of 28 different SHMT2 inhibitors that originate from the same skeleton. Major contributing residues from SHMT2 and chemical groups from the inhibitors were identified, and the binding energy of each residue was quantitatively determined, revealing essential features of the protein-inhibitor interaction. The most important contributing residue is Y105 of the B chain followed by L166 of the A chain. The calculated protein-ligand binding free energies are in good agreement with the experimental results and showed better correlation and smaller errors compared with those obtained using the conventional MM/GBSA with the normal mode method. These results may aid the rational design of more effective SHMT2 inhibitors.

Original languageEnglish (US)
Pages (from-to)3871-3878
Number of pages8
JournalJournal of Chemical Information and Modeling
Volume59
Issue number9
DOIs
StatePublished - Sep 23 2019

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Hydroxymethyl and Formyl Transferases
Alanine
Serine
Free energy
Protein Isoforms
Proteins
Scanning
energy
interaction
Binding energy
Metabolism
Amino acids
Entropy
Ligands
Cells
entropy
Carbon
cancer
Glycine
Group

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Study of SHMT2 Inhibitors and Their Binding Mechanism by Computational Alanine Scanning. / He, Liping; Bao, Jingxiao; Yang, Yunpeng; Dong, Suzhen; Zhang, Lujia; Qi, Yifei; Zhang, John.

In: Journal of Chemical Information and Modeling, Vol. 59, No. 9, 23.09.2019, p. 3871-3878.

Research output: Contribution to journalArticle

He, Liping ; Bao, Jingxiao ; Yang, Yunpeng ; Dong, Suzhen ; Zhang, Lujia ; Qi, Yifei ; Zhang, John. / Study of SHMT2 Inhibitors and Their Binding Mechanism by Computational Alanine Scanning. In: Journal of Chemical Information and Modeling. 2019 ; Vol. 59, No. 9. pp. 3871-3878.
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