Drug–Target Kinetics in Drug Discovery

Abstract

The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

<p>Fullerene Derivatives as Lung Cancer Cell Inhibitors: Investigation of Potential Descriptors Using QSAR Approaches</p>

“…Recent attention has been paid to the development of more selective anticancer agents to treat the cancer and to minimize the side effects. [10][11][12][13] The characteristic median lethal dose IC 50 of a certain compound acting on cancer cells and suppressing their proliferation by 50% is usually considered as a figure of merit in initial high-throughput screening of potential drug candidates in cell-based assays. 10 Nanotechnology has been widely used in biomedicine for the development of drug delivery systems, biological labels, protein detection, tumor destruction, etc.…”

“…[10][11][12][13] The characteristic median lethal dose IC 50 of a certain compound acting on cancer cells and suppressing their proliferation by 50% is usually considered as a figure of merit in initial high-throughput screening of potential drug candidates in cell-based assays. 10 Nanotechnology has been widely used in biomedicine for the development of drug delivery systems, biological labels, protein detection, tumor destruction, etc. 14 Tumors have immature and porous vasculature that provides an access for nanoparticles to enter the circulation system, 15 so nanoparticles can be used for selective delivery of drugs to the cancer cells.…”

Squaraine Dyes: Interaction with Bovine Serum Albumin to Investigate Supramolecular Adducts with Aggregation‐Induced Emission (AIE) Properties

“…Then, along with the potency of drug‐target binding interactions measured by the K d , binding kinetics is undoubtedly an essential issue in drug discovery. Both residence time and association rate constant are important parameters for in vivo efficacy and safety of drugs since they can help in understanding their mechanisms of action and structure–activity relationships …”

“…[3] Then, along with the potencyo fd rug-target binding interactions measured by the K d ,b inding kinetics is undoubtedly an essential issue in drug discovery.B oth residence time and association rate constant are important parameters for in vivo efficacy and safety of drugss ince they can help in understanding their mechanismso fa ction and structure-activity relationships. [4] Ag reat number of studies involving protein-dye interactions have been published so far [5] since the interesti nd eveloping new probes that can noncovalently bind proteins for their detection and sensingi sc onstantly growing. In particular, several fluorescent compounds (such as cyanine dyes and squaraine dyes [6,7] )e xhibit af luorescence" turn on" when bound to proteins which translate into an increase in quantum yield and lifetimedue to the changes in the environment.…”

Transient states and barriers from molecular simulations and milestoning theory: kinetics in ligand-protein recognition and compound design

“…Binding kinetics has become an important topic in molecular recognition because of the importance in fully understanding binding/unbinding and the growing awareness of the correlation between kinetics and drug efficacy [1][2][3][4][5] . Drug binding residence time, which can be estimated by a dissociation rate constant, 1/k off , is particularly important for determining the efficacy and selectivity of drug candidates.…”