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Binding selectivity-dependent molecular mechanism of inhibitors towards CDK2 and CDK6 investigated by multiple short molecular dynamics and free energy landscapes.
Wang, Lifei; Lu, Dan; Wang, Yan; Xu, Xiaoyan; Zhong, Peihua; Yang, Zhiyong.
Afiliación
  • Wang L; School of Science, Shandong Jiaotong University, Jinan, PR China.
  • Lu D; Department of Physics, Jiangxi Agricultural University, Nanchang, PR China.
  • Wang Y; School of Science, Shandong Jiaotong University, Jinan, PR China.
  • Xu X; School of Science, Shandong Jiaotong University, Jinan, PR China.
  • Zhong P; College of Computer Information and Engineering, Jiangxi Agriculture University, Nanchang, PR China.
  • Yang Z; Department of Physics, Jiangxi Agricultural University, Nanchang, PR China.
J Enzyme Inhib Med Chem ; 38(1): 84-99, 2023 Dec.
Article en En | MEDLINE | ID: mdl-36342274
Understanding selectivity-dependent molecular mechanism of inhibitors towards CDK2 over CDK6 is prominent for improving drug design towards the CDK family. Multiple short molecular dynamics (MD) simulations combined with MM-GBSA approach are adopted to investigate molecular mechanism on binding selectivity of inhibitors X64, X3A, and 4 AU to CDK2 and CDK6. The RMSF analysis and calculations of molecular surface areas indicate that local structural and global flexibility of CDK6 are stronger than that of CDK2. Based on dynamics cross-correlation maps (DCCMs), motion modes of CDK2 and CDK6 produce difference due to associations of X64, X3A, and 4 AU. The calculated binding free energies (BFEs) demonstrate that the compensation between binding enthalpy and entropy of X64, X34, and 4 AU is a key force driving selectivity of inhibitors towards CDK2 over CDK6. This work provides valuable information for designing highly selective inhibitors towards CDK2 and CDK6 and further promotes identification of efficient anticancer drugs in the future.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Simulación de Dinámica Molecular Idioma: En Revista: J Enzyme Inhib Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2023 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Simulación de Dinámica Molecular Idioma: En Revista: J Enzyme Inhib Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2023 Tipo del documento: Article Pais de publicación: Reino Unido