caa a22 4500 605513813 CHVBK 20210128100702.0 cr unu---uuuuu 210128e20151101xx s 000 0 eng 10.1007/s00894-015-2824-9 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2824-9 Towards predictive docking at aminergic G-protein coupled receptors [Elektronische Daten] [Jan Jakubík, Esam El-Fakahany, Vladimír Doležal] G protein-coupled receptors (GPCRs) are hard to crystallize. However, attempts to predict their structure have boomed as a result of advancements in crystallographic techniques. This trend has allowed computer-aided molecular modeling of GPCRs. We analyzed the performance of four molecular modeling programs in pose evaluation of re-docked antagonists / inverse agonists to 11 original crystal structures of aminergic GPCRs using an induced fit-docking procedure. AutoDock and Glide were used for docking. AutoDock binding energy function, GlideXP, Prime MM-GB/SA, and YASARA binding function were used for pose scoring. Root mean square deviation (RMSD) of the best pose ranged from 0.09 to 1.58Å, and median RMSD of the top 60 poses ranged from 1.47 to 3.83Å. However, RMSD of the top pose ranged from 0.13 to 7.33Å and ranking of the best pose ranged from the 1st to 60th out of 60 poses. Moreover, analysis of ligand-receptor interactions of top poses revealed substantial differences from interactions found in crystallographic structures. Bad ranking of top poses and discrepancies between top docked poses and crystal structures render current simple docking methods unsuitable for predictive modeling of receptor-ligand interactions. Prime MM-GB/SA optimized for 3NY9 by multiple linear regression did not work well at 3NY8 and 3NYA, structures of the same receptor with different ligands. However, 9 of 11 trajectories of molecular dynamics simulations by Desmond of top poses converged with trajectories of crystal structures. Key interactions were properly detected for all structures. This procedure also worked well for cross-docking of tested β2-adrenergic antagonists. Thus, this procedure represents a possible way to predict interactions of antagonists with aminergic GPCRs. Springer-Verlag Berlin Heidelberg, 2015 Induced-fit docking nationallicence Pose scoring nationallicence Molecular dynamics nationallicence Ligand-receptor interaction nationallicence Jakubík Jan Institute of Physiology, Academy of Sciences of the Czech Republic, 14220, Prague, Czech Republic aut El-Fakahany Esam Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, 55455, Minneapolis, MN, USA aut Doležal Vladimír Institute of Physiology, Academy of Sciences of the Czech Republic, 14220, Prague, Czech Republic aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/11(2015-11-01), 1-18 1610-2940 21:11<1 2015 21 894 https://doi.org/10.1007/s00894-015-2824-9 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2824-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Jakubík Jan Institute of Physiology, Academy of Sciences of the Czech Republic, 14220, Prague, Czech Republic aut NATIONALLICENCE 700 1- El-Fakahany Esam Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, 55455, Minneapolis, MN, USA aut NATIONALLICENCE 700 1- Doležal Vladimír Institute of Physiology, Academy of Sciences of the Czech Republic, 14220, Prague, Czech Republic aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/11(2015-11-01), 1-18 1610-2940 21:11<1 2015 21 894