Learning from Proteins and Drugs: Receptors That Mimic Biomedically Important Binding Motifs
Proteins are highly evolved, sophisticated machines which function together to maintain homeostasis in their hosts. While merely a collection of amino acids covalently bonded in a specific sequence, their wide variety of functions is truly remarkable. Of
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Abstract Proteins are highly evolved, sophisticated machines which function together to maintain homeostasis in their hosts. While merely a collection of amino acids covalently bonded in a specific sequence, their wide variety of functions is truly remarkable. Of course these covalent sequences are essential for proper function, but equally important for proper function are weak interactions: protein folding, enzyme-substrate interaction, and protein–protein communication are all controlled by forces weaker than covalent bonds and understanding these forces is fundamental in medicinal chemistry and drug design. Many inhibitory drugs mimic natural substrates for protein binding sites but inhibition of the substrate by mimicking the binding site is also possible. This mimicry and the biological consequences are under investigation. Keywords Aromatic interactions, Cation-pi interactions, Host-guest chemistry, Hydrogen bonds, Molecular Recognition
Contents 1 Introduction: Weak Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Anion Recognition by Carboxylic Acid Bioisosteres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Receptors That Mimic Natural Aromatic Cage Motifs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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F. Hof (*) and T. Pinter Department of Chemistry, University of Victoria, Victoria, BC, Canada V8W 3V6 e-mail: [email protected] S.A. Piletsky and M.J. Whitcombe (eds.), Designing Receptors for the Next Generation of Biosensors, Springer Series on Chemical Sensors and Biosensors (2013) 12: 33–52 DOI 10.1007/5346_2012_15, # Springer-Verlag Berlin Heidelberg 2012 Published online: 27 June 2012
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1 Introduction: Weak Interactions Weak interactions determine protein size and shape and are therefore an essential part of normal protein function. Discreet binding pockets and motifs that have evolved to be highly selective for only a very particular class of substrates come about as a result of a myriad of these non-covalent interactions. The helical shape of DNA is so because of an intricate combination of H-bond donor and acceptor pairs, stacking between the bases and solvation effects. Weak hydrogen bonding, electrostatic, and hydrophobic interactions play roles in all protein–substrate and protein–protein interactions. The most commonly observed weak interactions and arguably most important for normal protein function are hydrogen bonds. Ubiquitous in complex natural systems, almost all biological processes involve hydrogen bonding in some form or another and these i
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