Constructing Interconsistent, Reasonable, and Predictive Models for Both the Kinetic and Thermodynamic Properties of HIV-1 Protease Inhibitors.
Accumulated evidence suggests that the in vivo biological potency of a ligand is more strongly correlated with the binding/unbinding kinetics than the equilibrium thermodynamics of the protein-ligand interaction (PLI). However, the existing experimental and computational techniques are largely insufficient and limited in large-scale measurements or accurate predictions of the kinetic properties of PLI. In this work, elaborate efforts have been made to develop interconsistent, reasonable, and predictive models of the association rate constant (kon), dissociation rate constant (koff), and equilibrium dissociation constant (KD) of a series of HIV protease inhibitors with different structural skeletons. The results showed that nine Volsurf descriptors derived from water (OH2) and hydrophobic (DRY) probes are key molecular determinants for the kinetic and thermodynamic properties of HIV-1 protease inhibitors. To the best of our knowledge, this is the first time that interconsistent and reasonable models with strong prediction power have been established for both the kinetic and thermodynamic properties of HIV protease inhibitors.
Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University , Chongqing 400044, China.
Sujun
S
Qu
College of Bioengineering, Chongqing University , Chongqing 400044, China.
Shuheng
S
Huang
College of Bioengineering, Chongqing University , Chongqing 400044, China.
Xianchao
X
Pan
Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University , Chongqing 400044, China.|College of Bioengineering, Chongqing University , Chongqing 400044, China.
Li
L
Yang
Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University , Chongqing 400044, China.|College of Bioengineering, Chongqing University , Chongqing 400044, China.
Hu
H
Mei
D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D013816:Thermodynamics
D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1