The effect of desolvation on the binding of inhibitors to HIV-1 protease and cyclin-dependent kinases: Causes of resistance

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Fong, Clifford W.¹ 

[1] Eigenenergy, Adelaide, SA, Australia

关键词: QSAR model;    HIV-1 protease inhibitors;    CDK inhibitors;    Kinase binding;    Quantum mechanics;   

DOI  :  10.1016/j.bmcl.2016.05.080

来源: Elsevier

【 摘 要 】

Studies of the cyclin-dependent kinase inhibitors and HIV-1 protease inhibitors have confirmed that ligand-protein binding is dependent on desolvation effects. It has been found that a four parameter linear model incorporating desolvation energy, lipophilicity, dipole moment and molecular volume of the ligands is a good model to describe the binding between ligands and kinases or proteases. The resistance shown by MDR proteases to the anti-viral drugs is multi-faceted involving varying changes in desolvation, lipophilicity and dipole moment interaction compared to the non-resistant protease. Desolvation has been shown to be the dominant factor influencing the effect of inhibitors against the cyclin-dependent kinases, but lipophilicity and dipole moment are also significant factors. The model can differentiate between the inhibitory activity of CDK2/cycE, CDK1/cycB and CDK4/cycD enzymes. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

Free