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Review
. 2017 Jan 1;22:960-981.
doi: 10.2741/4527.

Understanding Ligand-Receptor Non-Covalent Binding Kinetics Using Molecular Modeling

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Free PMC article
Review

Understanding Ligand-Receptor Non-Covalent Binding Kinetics Using Molecular Modeling

Zhiye Tang et al. Front Biosci (Landmark Ed). .
Free PMC article

Abstract

Kinetic properties may serve as critical differentiators and predictors of drug efficacy and safety, in addition to the traditionally focused binding affinity. However the quantitative structure-kinetics relationship (QSKR) for modeling and ligand design is still poorly understood. This review provides an introduction to the kinetics of drug binding from a fundamental chemistry perspective. We focus on recent developments of computational tools and their applications to non-covalent binding kinetics.

Figures

Figure 1
Figure 1
Representative free energy profiles along the reaction coordinate for a fast binder and a slow binder. Ea is the activation energy of the forward process (association) and Ed is the activation energy of the backward process (dissociation).
Figure 2
Figure 2
The structure of β-cyclodextrin. The seven glucopyranose units are connected by α-1,4-glycosidic bonds.
Figure 3
Figure 3
The left is a superficial binding pose, and the right is a deeper binding pose with the ligand inside the cavity of β-cyclodextrin. The β-cyclodextrin is rendered with atom types while the ligand is rendered as green. In the left binding pose, the cavity of β-cyclodextrin is closed up by flipping of glucopyranose units. In the right binding pose, the cavity is open and some vacuum space is created.
Figure 4
Figure 4
Structure of the adrenergic receptor. The entrance of the binding tunnel is shown in blue. The binding site is shown in green. The first energy barrier is located above the blue sphere. The second energy barrier is between the blue and green regions.
Figure 5
Figure 5
Hydrogen-bond switches of ritonavir when binding to HIV-1 protease. (Top) The root mean square distance (RMSD) compared with the final bound state of ligand position (Red), the bound state of flaps (Green), and the tip distance (Black) and distance between two representative residues (Blue). (Middle) H-bond pairs between ritonavir and HIV-1 protease. (Bottom) Polar and nonpolar interactions during the binding process. The Figure is plotted using a trajectory from a 200 ns MD simulation with implicit-solvent model for ritonavir–HIVp association. Notably, the same behavior that shows similar hydrogen bond switches can be observed during binding processes in MD simulations using both implicit and explicit models.
Figure 6
Figure 6
Representative conformations of ritonavir when binding to HIV-1 protease. A, B, C, D, and E represent the MD snapshot for 0, 1.51, 4.04, 5.46, and 9.50 ns, respectively. The conformations are from the same 200 ns MD simulation with implicit-solvent model for ritonavir–HIVp association as in Figure 5.
Figure 7
Figure 7
Hopping Minima resulting association pathway for Cryptophane-E with Tetramethylammonium guest. Three natural motion paths, represented by yellow traces, connect four distinct minimum states. The ligand minimum states are colored, from red to yellow, according to their position along the association path. Hopping Minima provides both the translational motion of the ligand as well as the corresponding conformational changes of the host molecule.

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