Stereoselective and isozyme-selective drug interactions

A surprisingly large number of marketed drugs are racemic mixtures. The pharmacokinetic literature on racemic drugs contains a vast amount of information on drug–drug interactions derived from the measurement of total drug concentrations in plasma and urine. The appreciation of the role of stereochemistry in drug interactions with racemic warfarin resulted in a long-overdue scientific rigor being applied to the study of drug interactions. It also compelled us to recognize that much of the literature was uninterpretable. A better understanding of oxidative metabolism, particularly the complexity of the cytochrome P-450 family of enzymes, has also strengthened the scientific basis of drug interactions. We now recognize that investigators and clinicians must consider both stereoselectivity and isozyme selectivity in the study of drug interactions to understand the nature of the interaction so as to more effectively use new and potent drugs. © 1993 Wiley-Liss, Inc.     

Pharmacokinetic drug interactions of azoles

Drug-drug interactions are a major concern with triazoles. Azoles are potent metabolic inhibitors and interactions commonly occur via metabolizing enzymes (ie, cytochrome P450 isoenzyme superfamily) or drug transporters (ie, P-glycoprotein). However, the clinical relevance of these interactions may vary upon the azole involved and upon the “target” drug. Azoles may also be under influence of and become targets of metabolic drug-drug interactions. Potential interactions between antifungal agents and over-the-counter or alternative medicines and herbs should not be underestimated. Here, we provide a comprehensive overview of different types of pharmacokinetic drug interactions involving azoles with selected examples.     

Kinetic simulation of anticancer drug interactions

A model is described that simulates the biochemical pathways of folate and nucleotide metabolism involved in DNA precursor biosynthesis. Examples are given of use of the model to study various aspects of the biochemical pharmacology of antitumour drugs. Modelling may be done in two ways: detailed simulation of all variables may be conducted for short time periods (<6 h of real time); alternatively, by assuming that concentrations of rapidly interconvertible metabolites remain close to steady-state proportions, time periods of several days may be modelled, facilitating simulation of cell growth in presence of drugs. Experiments designed to test predictions for these various types of study are described.     

Modeling sequence-sequence interactions for drug response

MOTIVATION: Genetic interactions or epistasis may play an important role in the genetic etiology of drug response. With the availability of large-scale, high-density single nucleotide polymorphism markers, a great challenge is how to associate haplotype structures and complex drug response through its underlying pharmacodynamic mechanisms. RESULTS: We have derived a general statistical model for detecting an interactive network of DNA sequence variants that encode pharmacodynamic processes based on the haplotype map constructed by single nucleotide polymorphisms. The model was validated by a pharmacogenetic study for two predominant beta-adrenergic receptor (betaAR) subtypes expressed in the heart, beta1AR and beta2AR. Haplotypes from these two receptors trigger significant interaction effects on the response of heart rate to different dose levels of dobutamine. This model will have implications for pharmacogenetic and pharmacogenomic research and drug discovery. AVAILABILITY: A computer program written in Matlab can be downloaded from the webpage of statistical genetics group at the University of Florida. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.     

Depletion interactions in polymer solutions promote red blood cell adhesion to albumin-coated surfaces

The effects of concentration and molecular weight of neutral dextrans on the adhesion of human red blood cells (RBC) to albumin-coated glass have been investigated using a parallel-plate flow chamber. Results indicate that the adhesion is markedly increased in the presence of 70 kDa and 500 kDa dextran, with this increase reflected by both the number of cells adhering and the strength of the adhesion. This increased adhesiveness is attributed to reduced surface concentrations of the large polymers and hence attractive forces due to depletion interaction. Depletion interaction brings the adjacent surfaces closer, leading to an increased number of binding sites available to the cell and thus more efficient and stronger adhesion of single cells. Our results suggest that depletion might play a role in other specific cell-cell or cell-surface interactions via initiating close contacts to allow specific binding.     

Unique interactions between the chromophore and glutamate 16 lead to far‐red emission in a red fluorescent protein

mPlum is a far‐red fluorescent protein with emission maximum at ～650 nm and was derived by directed evolution from DsRed. Two residues near the chromophore, Glu16 and Ile65, were previously revealed to be indispensable for the far‐red emission. Ultrafast time‐resolved fluorescence emission studies revealed a time dependent shift in the emission maximum, initially about 625 nm, to about 650 nm over a period of 500 ps. This observation was attributed to rapid reorganization of the residues solvating the chromophore within mPlum. Here, the crystal structure of mPlum is described and compared with those of two blue shifted mutants mPlum‐E16Q and ‐I65L. The results suggest that both the identity and precise orientation of residue 16, which forms a unique hydrogen bond with the chromophore, are required for far‐red emission. Both the far‐red emission and the time dependent shift in emission maximum are proposed to result from the interaction between the chromophore and Glu16. Our findings suggest that significant red shifts might be achieved in other fluorescent proteins using the strategy that led to the discovery of mPlum.     

Checkpoints: how to flag up double-strand breaks

How checkpoint pathways recognise double-strand breaks has long been a mystery. Recent studies have found that two distinct checkpoint protein complexes associate independently with chromatin at the sites of DNA damage. Why do two distinct mechanisms recognise strand lesions, and what does this tell us about the checkpoint pathways?     

Protein interactions in 3D: From interface evolution to drug discovery

Over the past 10years, much research has been dedicated to the understanding of protein interactions. Large-scale experiments to elucidate the global structure of protein interaction networks have been complemented by detailed studies of protein interaction interfaces. Understanding the evolution of interfaces allows one to identify convergently evolved interfaces which are evolutionary unrelated but share a few key residues and hence have common binding partners. Understanding interaction interfaces and their evolution is an important basis for pharmaceutical applications in drug discovery. Here, we review the algorithms and databases on 3D protein interactions and discuss in detail applications in interface evolution, drug discovery, and interface prediction.