The effect of desolvation on the binding of inhibitors to HIV-1 protease and cyclin-dependent kinases: Causes of resistance.
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.
Eigenenergy, Adelaide, South Australia, Australia. Electronic address: cwfong@internode.on.net.
Clifford W
CW
Fong
D001665:Binding Sites / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016333:HIV Protease / Q000378:metabolism*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
CDK inhibitors; HIV-1 protease inhibitors; Kinase binding; QSAR model; Quantum mechanics