Main poorly understood, however, especially when compared with the well-known factors that affect binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control drug–receptor binding kinetics at the molecular level – molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects – and discuss several possible approaches for the rational design of drugs with desired binding kinetics. Drug binding and unbinding rates impact efficacy and safety The molecular determinants of binding kinetics are poorly understood Determinants include molecular size, conformational fluctuations, electrostatic interactions, and hydrophobic effects Recent experimental and computational advances facilitate elucidation of these molecular determinants These determinants suggest several possible approaches to rational optimization of drug binding kinetics.
Related Content
Pharmacogenomics and Translational Simulations to Bridge Indications for an Anti-Interferon-α Receptor Antibody
A type I interferon (IFN) gene signature shared by systemic lupus erythematous (SLE) and systemic sclerosis (SSc) was used to evaluate an anti-type I IFN-α receptor (IFN-αR) monoclonal antibody, MEDI-546, in a phase I trial in SSc. MEDI-546 suppressed IFN signature in blood and sk...


A single glycine in extracellular loop 1 is the critical determinant for pharmacological specificity of dopamine D2 and D3 receptors
Subtype-selective agents for the dopamine D3 receptor (D3R) have been considered as potential medications for drug addiction and other neuropsychiatric disorders. Medicinal chemistry efforts have led to the discovery of 4-phenylpiperazine derivatives that are >100-fold selective for D3R over D2R,...
Molecular determinants of orexin receptor-arrestin-ubiquitin complex formation
The orexin system regulates a multitude of key physiological processes, particularly involving maintenance of metabolic homeostasis. Consequently there is considerable potential for pharmaceutical development for the treatment of disorders from narcolepsy to metabolic syndrome. It acts through th...


High end GPCR design: crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks
G Protein-Coupled Receptors (GPCRs) are a large family of therapeutically important proteins and as diverse X-ray structures become available it is increasingly possible to leverage structural information for rational drug design. We present herein approaches that use explicit water networks comb...
Transporter-Mediated Drug–Drug Interactions with Oral Antidiabetic Drugs
Uptake transporters (e.g., members of the SLC superfamily of solute carriers) and export proteins (e.g., members of the ABC transporter superfamily) are important determinants for the pharmacokinetics of drugs. Alterations of drug transport due to concomitantly administered drugs that interfere w...

Anti-obesity target MCHR1 is allosterically inhibited by 8-methylquinoline derivatives possessing subnanomolar-binding and long residence times
PurposeMelanin-concentrating hormone receptor 1 (MCHR1) antagonists are being considered as anti-obesity agents. The present study reports a new class of MCHR1 antagonists with an 8-methylquinoline scaffold. The molecular mechanism of MCHR1 blockade by these antagonists was examined. Experimental...
Biomarker-Driven Therapeutic Management of Alzheimer’s Disease: Establishing the Foundations
Biomarkers are characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Amyloid measures become abnormal early in the Alzheimer’s disease process and have only ...

A DFT and Semiempirical Model-Based Study of Opioid Receptor Affinity and Selectivity in a Group of Molecules with a Morphine Structural Core
We report the results of a search for model-based relationships between mu, delta, and kappa opioid receptor binding affinity and molecular structure for a group of molecules having in common a morphine structural core. The wave functions and local reactivity indices were obtained at the ZINDO/1 ...
Molecular Dissection of Lubeluzole Use-dependent Block of Voltage-gated Sodium Channels Discloses New Therapeutic Potentials
Lubeluzole, which acts on various targets in vitro, including voltage-gated sodium channels (NaChs), was initially proposed as neuroprotectant. Lubeluzole structure contains a benzothiazole moiety (R-like) related to riluzole and a phenoxy-propranol-amine moiety (A-core) recalling propranolol. Bo...

The Effect of Novel Promoter Variants in MATE1 and MATE2 on the Pharmacokinetics and Pharmacodynamics of Metformin
Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.–66TC...