Adaptable Small Ligand of CYP1 Enzymes for Use in Understanding the Structural Features Determining Isoform Selectivity

Joo Youn Lee; Hyunkyung Cho; Sundarapandian Thangapandian; Chaemin Lim; Young Jin Chun; Yoonji Lee; Sun Choi; Sanghee Kim

doi:10.1021/acsmedchemlett.8b00409

Adaptable Small Ligand of CYP1 Enzymes for Use in Understanding the Structural Features Determining Isoform Selectivity

Joo Youn Lee, Hyunkyung Cho, Sundarapandian Thangapandian, Chaemin Lim, Young Jin Chun, Yoonji Lee, Sun Choi, Sanghee Kim

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Although several families of compounds have been identified as scaffolds for inhibitors of the CYP1 family, the isoform selectivity determining structural features has not been fully clarified at the molecular interaction level. We studied the CYP1 isoform selectivity for stilbenoid inhibitors using integrated induced fit docking and molecular dynamics simulations. The hydrophobic interactions with the specific phenylalanine residues in the F helix are correlated with inhibitory potency in the CYP1 family. Through this study, we found that the adaptable, small, and semirigid ligand is a promising starting point for the development of isoform-selective inhibitors and investigation of selectivity-determining features.

Original language	English
Pages (from-to)	1247-1252
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	12
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00409
State	Published - 13 Dec 2018

Bibliographical note

Funding Information:
This work was supported by the Mid-Career Researcher Program (NRF-2016R1A2A1A05005375) of the National Research Foundation (NRF) grant funded by the Korea government (MSIP).

Publisher Copyright:
© 2018 American Chemical Society.

Keywords

Cytochrome P450
Isoform selectivity
Molecular dynamics
trans-Stilbenoids

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10.1021/acsmedchemlett.8b00409

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abstract = "Although several families of compounds have been identified as scaffolds for inhibitors of the CYP1 family, the isoform selectivity determining structural features has not been fully clarified at the molecular interaction level. We studied the CYP1 isoform selectivity for stilbenoid inhibitors using integrated induced fit docking and molecular dynamics simulations. The hydrophobic interactions with the specific phenylalanine residues in the F helix are correlated with inhibitory potency in the CYP1 family. Through this study, we found that the adaptable, small, and semirigid ligand is a promising starting point for the development of isoform-selective inhibitors and investigation of selectivity-determining features.",

keywords = "Cytochrome P450, Isoform selectivity, Molecular dynamics, trans-Stilbenoids",

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AU - Cho, Hyunkyung

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AU - Lim, Chaemin

AU - Chun, Young Jin

AU - Lee, Yoonji

AU - Choi, Sun

AU - Kim, Sanghee

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N2 - Although several families of compounds have been identified as scaffolds for inhibitors of the CYP1 family, the isoform selectivity determining structural features has not been fully clarified at the molecular interaction level. We studied the CYP1 isoform selectivity for stilbenoid inhibitors using integrated induced fit docking and molecular dynamics simulations. The hydrophobic interactions with the specific phenylalanine residues in the F helix are correlated with inhibitory potency in the CYP1 family. Through this study, we found that the adaptable, small, and semirigid ligand is a promising starting point for the development of isoform-selective inhibitors and investigation of selectivity-determining features.

AB - Although several families of compounds have been identified as scaffolds for inhibitors of the CYP1 family, the isoform selectivity determining structural features has not been fully clarified at the molecular interaction level. We studied the CYP1 isoform selectivity for stilbenoid inhibitors using integrated induced fit docking and molecular dynamics simulations. The hydrophobic interactions with the specific phenylalanine residues in the F helix are correlated with inhibitory potency in the CYP1 family. Through this study, we found that the adaptable, small, and semirigid ligand is a promising starting point for the development of isoform-selective inhibitors and investigation of selectivity-determining features.

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Adaptable Small Ligand of CYP1 Enzymes for Use in Understanding the Structural Features Determining Isoform Selectivity

Abstract

Bibliographical note

Keywords

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