title: Enzyme Tunnels and Gates As Relevant Targets in Drug Design.
abstract: Many enzymes contain tunnels and gates that are essential to their function. Gates reversibly switch between open and closed conformations and thereby control the traffic of small molecules-substrates, products, ions, and solvent molecules-into and out of the enzyme's structure via molecular tunnels. Many transient tunnels and gates undoubtedly remain to be identified, and their functional roles and utility as potential drug targets have received comparatively little attention. Here, we describe a set of general concepts relating to the structural properties, function, and classification of these interesting structural features. In addition, we highlight the potential of enzyme tunnels and gates as targets for the binding of small molecules. The different types of binding that are possible and the potential pharmacological benefits of such targeting are discussed. Twelve examples of ligands bound to the tunnels and/or gates of clinically relevant enzymes are used to illustrate the different binding modes and to explain some new strategies for drug design. Such strategies could potentially help to overcome some of the problems facing medicinal chemists and lead to the discovery of more effective drugs.
authors.affiliation: Loschmidt Laboratories, Faculty of Science, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, RECETOX, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Marques
authors.affiliation: Loschmidt Laboratories, Faculty of Science, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, RECETOX, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.|International Centre for Clinical Research, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Daniel
authors.affiliation: Loschmidt Laboratories, Faculty of Science, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, RECETOX, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.|International Centre for Clinical Research, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Buryska
authors.affiliation: Loschmidt Laboratories, Faculty of Science, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, RECETOX, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.|International Centre for Clinical Research, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Prokop
authors.affiliation: Loschmidt Laboratories, Faculty of Science, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, RECETOX, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.|International Centre for Clinical Research, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Brezovsky
authors.affiliation: Loschmidt Laboratories, Faculty of Science, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, RECETOX, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.|International Centre for Clinical Research, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Damborsky
mesh_terms: D015195:Drug Design; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy
chemical_list: D004798:Enzymes
keywords: drug binding; drug design; protein gates; protein tunnels; selectivity; specificity