Effect of Substituents in Different Positions of Aminothiazole Hinge-Binding Scaffolds on Inhibitor-CDK2 Association Probed by Interaction Entropy Method

Jianzhong Chen, Xingyu Wang, John Zhang, Tong Zhu

Research output: Contribution to journalArticle

Abstract

Recently, CDK2 has been a promising target of drug development for the treatment of the myriad of various human diseases. Molecular dynamics (MD) simulations are integrated with an efficient interaction entropy method to probe the effect of substitutions at S1 and S2 positions of the aminothiazole hinge-binding scaffold (1-{4-amino-2-(alkyl(o-aryl)amino)thiazol-5-yl}arylmethanones) on binding of inhibitors to CDK2. The results suggest that a para-sulfonamide moiety or a meta-amino group of a phenyl ring introduced into S1 and S2 of the aminothiazole hinge-binding scaffold could not only improve the van der Waals interactions of inhibitors with CDK2, but also strengthen their electrostatic interactions. The hot interaction spots of inhibitors with residues of CDK2 were identified by performing scanning of hydrophobic contacts and hydrogen bond contacts of inhibitors with CDK2 on MD trajectories. The results show that the aminothiazole hinge-binding scaffold not only generates stable hydrophobic contacts with conserved residues V18 and L134, but also form stable hydrogen bond contacts with conserved residues E81 and L83. Among the current substitutions, a para-sulfonamide moiety or a meta-amino group of a phenyl ring at S1 and S2 of the aminothiazole hinge-binding scaffold displays potential to improve the binding ability of inhibitors to CDK2. We expect that this study can contribute significant guidance to design potent inhibitors targeting CDK2.

Original languageEnglish (US)
Pages (from-to)18052-18064
Number of pages13
JournalACS Omega
Volume3
Issue number12
DOIs
StatePublished - Dec 21 2018

Fingerprint

Hinges
Scaffolds
Entropy
Sulfonamides
Molecular dynamics
Hydrogen bonds
Substitution reactions
Coulomb interactions
Display devices
Trajectories
Scanning
Computer simulation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Effect of Substituents in Different Positions of Aminothiazole Hinge-Binding Scaffolds on Inhibitor-CDK2 Association Probed by Interaction Entropy Method. / Chen, Jianzhong; Wang, Xingyu; Zhang, John; Zhu, Tong.

In: ACS Omega, Vol. 3, No. 12, 21.12.2018, p. 18052-18064.

Research output: Contribution to journalArticle

@article{274561dab0f34854af09f8eda66067b3,
title = "Effect of Substituents in Different Positions of Aminothiazole Hinge-Binding Scaffolds on Inhibitor-CDK2 Association Probed by Interaction Entropy Method",
abstract = "Recently, CDK2 has been a promising target of drug development for the treatment of the myriad of various human diseases. Molecular dynamics (MD) simulations are integrated with an efficient interaction entropy method to probe the effect of substitutions at S1 and S2 positions of the aminothiazole hinge-binding scaffold (1-{4-amino-2-(alkyl(o-aryl)amino)thiazol-5-yl}arylmethanones) on binding of inhibitors to CDK2. The results suggest that a para-sulfonamide moiety or a meta-amino group of a phenyl ring introduced into S1 and S2 of the aminothiazole hinge-binding scaffold could not only improve the van der Waals interactions of inhibitors with CDK2, but also strengthen their electrostatic interactions. The hot interaction spots of inhibitors with residues of CDK2 were identified by performing scanning of hydrophobic contacts and hydrogen bond contacts of inhibitors with CDK2 on MD trajectories. The results show that the aminothiazole hinge-binding scaffold not only generates stable hydrophobic contacts with conserved residues V18 and L134, but also form stable hydrogen bond contacts with conserved residues E81 and L83. Among the current substitutions, a para-sulfonamide moiety or a meta-amino group of a phenyl ring at S1 and S2 of the aminothiazole hinge-binding scaffold displays potential to improve the binding ability of inhibitors to CDK2. We expect that this study can contribute significant guidance to design potent inhibitors targeting CDK2.",
author = "Jianzhong Chen and Xingyu Wang and John Zhang and Tong Zhu",
year = "2018",
month = "12",
day = "21",
doi = "10.1021/acsomega.8b02354",
language = "English (US)",
volume = "3",
pages = "18052--18064",
journal = "ACS Omega",
issn = "2470-1343",
publisher = "American Chemical Society",
number = "12",

}

TY - JOUR

T1 - Effect of Substituents in Different Positions of Aminothiazole Hinge-Binding Scaffolds on Inhibitor-CDK2 Association Probed by Interaction Entropy Method

AU - Chen, Jianzhong

AU - Wang, Xingyu

AU - Zhang, John

AU - Zhu, Tong

PY - 2018/12/21

Y1 - 2018/12/21

N2 - Recently, CDK2 has been a promising target of drug development for the treatment of the myriad of various human diseases. Molecular dynamics (MD) simulations are integrated with an efficient interaction entropy method to probe the effect of substitutions at S1 and S2 positions of the aminothiazole hinge-binding scaffold (1-{4-amino-2-(alkyl(o-aryl)amino)thiazol-5-yl}arylmethanones) on binding of inhibitors to CDK2. The results suggest that a para-sulfonamide moiety or a meta-amino group of a phenyl ring introduced into S1 and S2 of the aminothiazole hinge-binding scaffold could not only improve the van der Waals interactions of inhibitors with CDK2, but also strengthen their electrostatic interactions. The hot interaction spots of inhibitors with residues of CDK2 were identified by performing scanning of hydrophobic contacts and hydrogen bond contacts of inhibitors with CDK2 on MD trajectories. The results show that the aminothiazole hinge-binding scaffold not only generates stable hydrophobic contacts with conserved residues V18 and L134, but also form stable hydrogen bond contacts with conserved residues E81 and L83. Among the current substitutions, a para-sulfonamide moiety or a meta-amino group of a phenyl ring at S1 and S2 of the aminothiazole hinge-binding scaffold displays potential to improve the binding ability of inhibitors to CDK2. We expect that this study can contribute significant guidance to design potent inhibitors targeting CDK2.

AB - Recently, CDK2 has been a promising target of drug development for the treatment of the myriad of various human diseases. Molecular dynamics (MD) simulations are integrated with an efficient interaction entropy method to probe the effect of substitutions at S1 and S2 positions of the aminothiazole hinge-binding scaffold (1-{4-amino-2-(alkyl(o-aryl)amino)thiazol-5-yl}arylmethanones) on binding of inhibitors to CDK2. The results suggest that a para-sulfonamide moiety or a meta-amino group of a phenyl ring introduced into S1 and S2 of the aminothiazole hinge-binding scaffold could not only improve the van der Waals interactions of inhibitors with CDK2, but also strengthen their electrostatic interactions. The hot interaction spots of inhibitors with residues of CDK2 were identified by performing scanning of hydrophobic contacts and hydrogen bond contacts of inhibitors with CDK2 on MD trajectories. The results show that the aminothiazole hinge-binding scaffold not only generates stable hydrophobic contacts with conserved residues V18 and L134, but also form stable hydrogen bond contacts with conserved residues E81 and L83. Among the current substitutions, a para-sulfonamide moiety or a meta-amino group of a phenyl ring at S1 and S2 of the aminothiazole hinge-binding scaffold displays potential to improve the binding ability of inhibitors to CDK2. We expect that this study can contribute significant guidance to design potent inhibitors targeting CDK2.

UR - http://www.scopus.com/inward/record.url?scp=85059234212&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059234212&partnerID=8YFLogxK

U2 - 10.1021/acsomega.8b02354

DO - 10.1021/acsomega.8b02354

M3 - Article

VL - 3

SP - 18052

EP - 18064

JO - ACS Omega

JF - ACS Omega

SN - 2470-1343

IS - 12

ER -