The binding of a ligand molecule to a protein is often accompanied by conformational changes of the protein. A central question is whether the ligand induces the conformational change (induced-fit), or rather selects and stabilizes a complementary conformation from a pre-existing equilibrium of ground and excited states of the protein (selected-fit). We consider here the binding kinetics in a simple four-state model of ligand-protein binding. In this model, the protein has two conformations, which can both bind the ligand. The first conformation is the ground state of the protein when the ligand is off, and the second conformation is the ground state when the ligand is bound. The induced-fit mechanism corresponds to ligand binding in the unbound ground state, and the selected-fit mechanism to ligand binding in the excited state. We find a simple, characteristic difference between the on- and off-rates in the two mechanisms if the conformational relaxation into the ground states is fast. In the case of selected-fit binding, the on-rate depends on the conformational equilibrium constant, while the off-rate is independent. In the case of induced-fit binding, in contrast, the off-rate depends on the conformational equilibrium, while the on-rate is independent. Whether a protein binds a ligand via selected-fit or induced-fit thus may be revealed by mutations far from the protein's binding pocket, or other "perturbations" that only affect the conformational equilibrium. In the case of selected-fit, such mutations will only change the on-rate, and in the case of induced-fit, only the off-rate.

Selected-fit versus induced-fit protein binding: Kinetic differences and mutational analysis

Objectives. To assess the breadth, depth, and perceived importance of pharmacogenomics instruction and level of faculty development in this area in schools and colleges of pharmacy in the United St...

Pharmacogenomics in the curricula of colleges and schools of pharmacy in the United States.

Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible. This opposes the prevailing hypothesis of drug permeation through biological membranes, which integrates the contribution of multiple permeation mechanisms, including both carrier-mediated and passive lipoidal diffusion, depending on the compound's properties, membrane properties, and solution properties. The prevailing hypothesis of drug permeation continues to be successful for application and prediction in drug development. Proponents of the carrier-mediated only concept argue against passive lipoidal diffusion. However, the arguments are not supported by broad pharmaceutics literature. The carrier-mediated only concept lacks substantial supporting evidence and successful applications in drug development.

Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition.

Personalized nanomedicine advancements for stem cell tracking.

Evidence-based medicine (EBM) and personalized medicine (PM) are fashionable concepts frequently endorsed by medical and pharmacological journals. Everyone appears to agree that both should be implemented in the real world of clinical practice as soon as possible. The author believes that it will no

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Evidence-based medicine versus personalized medicine: are they enemies?

The branch of pharmacology we now call 'drug metabolism', the consideration of the enzymes and procesess determining the disposition of drugs in the body, emerged in the 1840s on the continent of Europe, but British science made little or no contribution until the 1920s. From this point on, the development of the field through the 20th century was shaped to a very significant extent by a series of influential British workers, whose contributions were of global significance and who can now be seen as fathers of the subject. Since the 1950s, and gaining pace inexorably from the 1970s, the significance of drug metabolism to human therapeutics has been greatly added to by the emergence of pharmacogenetics, clinically important hereditary variation in response to drugs, which underpins the current emphasis on personalised medicine. This review examines the British contributions to both these fields through the lives of seven key contributors and attempts to place their work both in the context of its time and its lasting influence.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0706466

Drug metabolism and pharmacogenetics: the British contribution to fields of international significance

This review continues a general presentation of the principles of stereochemistry with special reference to the medicinal sciences. Here, we discuss and illustrate molecular and clinical phenomena of stereoselectivity in pharmacological effects, namely activity differences between stereoisomers, principally enantiomers. The review begins with didactic models of chiral recognition, with a main focus on the early model of Easson and Stedman. There follows a Molecular Modeling (MM) and Molecular Dynamics (MD) depiction of the differential interaction of the enantiomers of hyoscyamine with cholinergic muscarinic receptors. The next section is devoted to various rationalizations in stereoselective pharmacological activity, e.g., the influence of optical purity on enantioselectivity, Pfeiffer's rule, and eudismic analysis. The review ends with selected examples taken from various fields of preclinical and clinical pharmacology, of differences between stereoisomers in terms of drug absorption, distribution, and excretion. The influence of conformational factor in molecular pharmacology will be discussed in Part 6, while stereoselective aspects of xenobiotic metabolism will be reviewed in Parts 7 and 8.

Organic stereochemistry. Part 5 : Stereoselectivity in molecular and clinical pharmacology

There have been major developments in our understanding of the ways in which genetic variation among individuals in a population can affect responses to drugs, and use of such information can improve the safety and efficacy of medicines. The brief review summarizes the emergence of modern pharmacogenetics, illustrating the importance of the field using the CYP 2D6 polymorphism as a paradigm. These pharmacogenetic polymorphisms are compared and contrasted with the long-established inborn errors of amino acid biochemistry, exemplified by phenylketonuria, suggesting ways in which the approaches of pharmacogenetics might inform the safe and effective use of amino acids as food additives and supplements.

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Pharmacogenetics and individual variation in the range of amino acid adequacy: The biological aspects

The effect of EGF and the comitogen, norepinephrine, on the proliferative responses of fresh and cryopreserved rat and mouse hepatocytes.

Foreword: D. Seebach Preface: The Editors Part 1: Symmetry Elements and Operations, Classification of Stereoisomers (B. Testa, G. Vistoli, and A. Pedretti) Part 2: Stereoisomerism Resulting from One or Several Stereogenic Centers (B. Testa) Part 3: Other Stereogenic Elements: Axes of Chirality, Planes of Chirality, Helicity, and (E,Z)-Diastereoisomerism (B. Testa) Part 4: Isomerisms about Single Bonds and in Cyclic Systems (B. Testa, G. Vistoli, and A. Pedretti) Part 5: Stereoselectivity in Molecular and Clinical Pharmacology (B. Testa, G. Vistoli, A. Pedretti, and J. Caldwell) Part 6: The Conformation Factor in Molecular Pharmacology (G. Vistoli, B. Testa, and A. Pedretti) Part 7: The Concept of Substrate Stereoselectivity in Biochemistry and Xenobiotic Metabolism (B. Testa) Part 8: Prostereoisomerism and the Concept of Product Stereoselectivity in Biochemistry and Xenobiotic Metabolism (B. Testa) Part 9: Molecular Chirality in Chemistry and Biology: Historical Milestones (J. Gal) Glossary Index

John Caldwell

Papers

Drug metabolism and pharmacogenetics: the British contribution to fields of international significance

Organic stereochemistry. Part 5 : Stereoselectivity in molecular and clinical pharmacology

Pharmacogenetics and individual variation in the range of amino acid adequacy: The biological aspects

The effect of EGF and the comitogen, norepinephrine, on the proliferative responses of fresh and cryopreserved rat and mouse hepatocytes.

Organic Stereochemistry: Guiding Principles and Bio‐Medicinal Relevance