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.

International Centre for Clinical Research St Anne's University Hospital Pekarska 53 656 91 Brno Czech Republic

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

References provided by Crossref.org

Large-scale annotation of biochemically relevant pockets and tunnels in cognate enzyme-ligand complexes

Fully automated virtual screening pipeline of FDA-approved drugs using Caver Web

Screening of world approved drugs against highly dynamical spike glycoprotein of SARS-CoV-2 using CaverDock and machine learning

Fast Screening of Inhibitor Binding/Unbinding Using Novel Software Tool CaverDock

Caver Web 1.0: identification of tunnels and channels in proteins and analysis of ligand transport

CAVER Analyst 2.0: analysis and visualization of channels and tunnels in protein structures and molecular dynamics trajectories