Structure modeling of γ-aminobutyric acid transporters - Molecular basics of ligand selectivity.

γ-Aminobutyric acid transporters are responsible for regulating the GABA level in the synaptic cleft. In this way, they affect GABA-ergic transmission which is important for the proper functioning of the central nervous system. The exact structure of GABA transporters is still unknown, which hinders the design of new, potent and selective inhibitors. For these reasons, we decided to create models of all types of human gamma-aminobutyric acid transporters. They were built based on crystal structures of related proteins from the SLC6 family using homology modeling methods. The reliability of the received models has been confirmed by a number of tools assessing the quality of protein models. To determine the ligand binding mode and indicate the amino acids responsible for selectivity, docking studies and molecular dynamics simulations were performed. The amino acids lining the bottom of the main binding site have a major impact on the selective ligand binding. In addition, an important element is the non-helical fragment of the transmembrane domain 10, and several amino acids within the vestibule of the transporters, which affect its volume. To check whether obtained models are suitable to distinguish active compounds from inactive ones, enrichment plots were prepared. Results suggest that our models may be useful in the search for new inhibitors of GABA transporters of the desired selectivity.