Abstract
The lifetime of a binary drug–target complex is increasingly acknowledged as an important parameter for drug efficacy and safety. With a better understanding of binding kinetics and better knowledge about kinetic parameter optimization, intentionally induced prolongation of the drug–target residence time through structural changes of the ligand could become feasible. In this study we assembled datasets from 21 publications and the K4DD (Kinetic for Drug Discovery) database to conduct large scale data analysis. This resulted in 3812 small molecules annotated to 78 different targets from five protein classes (GPCRs: 273, kinases: 3238, other enzymes: 240, HSPs: 160, ion channels: 45). Performing matched molecular pair (MMP) analysis to further investigate the structure–kinetic relationship (SKR) in this data collection allowed us to identify a fundamental contribution of a ligand's polarity to its association rate, and in selected cases, also to its dissociation rate. However, we furthermore observed that the destabilization of the transition state introduced by increased polarity is often accompanied by simultaneous destabilization of the ground state resulting in an unaffected or even worsened residence time. Supported by a set of case studies, we provide concepts on how to alter ligands in ways to trigger on-rates, off-rates, or both.
Highlights
Performing matched molecular pair (MMP) analysis to further investigate the structure–kinetic relationship (SKR) in this data collection allowed us to identify a fundamental contribution of a ligand's polarity to its association rate, and in selected cases, to its dissociation rate
The kinetic dataset KIND (KINetic Dataset) contains a total of 3812 structures and their kinetic data triplets. It has been compiled from 21 publications[16,19,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42] and the K4DD database
We previously demonstrated that changes in a molecule's polarity are the major factor for kon alteration in Hsp90.24 In order to investigate whether this hypothesis can be generalized across targets, we analyzed KIND by focusing on the MMPs with the highest differences in kon values
Summary
Importance of kinetic parameters in drug designMultiple studies on the kinetic behavior of small molecules show how the lifetime of a binary drug–target complex is inevitable for translation into in vivo efficacy.[1,2,3,4,5,6] The so-called drug residence time (τ), which is the time a drug spends bound to its protein target, influences efficacy, but is linked to toxicity[7] and off-target activity.[8,9] The life span of this complex does need to be of minimal duration to achieve a certain function, and, in particular cases, should not exceed a certain time for optimal function.[10]. The off-rate, koff, is the dissociation rate, which is the parameter most scientific publications have focused on It is the inverse of the residence time, and a measure for how long a compound remains bound to its protein target. The off-rate koff can be influenced in 2 ways: i) stabilization of the ground state[12] and/or ii) destabilization of the transition state.[13,14,15] In both cases, the energy difference between the bound state and the transition state needs to be increased to reach higher τ values. Increasing the energy barrier to overcome the transition state results in a slower binding event (the kon value gets smaller), and in a prolonged residence time (assuming two different molecules display similar binding affinities) and the system is in an equilibrium state (where KD = koff/kon). Herenbrink et al published that on-rates are the determining factor in GPCR downstream pathway prioritization, leading to different biological outcomes.[23]
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