Influence of Protonation, Tautomeric, and Stereoisomeric States on Protein−Ligand Docking Results

Abstract

In this work, we present a systematical investigation of the influence of ligand protonation states, stereoisomers, and tautomers on results obtained with the two protein-ligand docking programs GOLD and PLANTS. These different states were generated with a fully automated tool, called SPORES (Structure PrOtonation and Recognition System). First, the most probable protonations, as defined by this rule based system, were compared to the ones stored in the well-known, manually revised CCDC/ASTEX data set. Then, to investigate the influence of the ligand protonation state on the docking results, different protonation states were created. Redocking and virtual screening experiments were conducted demonstrating that both docking programs have problems in identifying the correct protomer for each complex. Therefore, a preselection of plausible protomers or the improvement of the scoring functions concerning their ability to rank different molecules/states is needed. Additionally, ligand stereoisomers were tested for a subset of the CCDC/ASTEX set, showing similar problems regarding the ranking of these stereoisomers as the ranking of the protomers.

Construction and Optimization of Structure-Based Virtual Screening Protocols to Identify Cyclooxygenase-1 Inhibitors Using Open Babel, Spores and Plants

“…The similar protocol was subsequently employed by Hayun et al [8] to design some COX-2 inhibitors. Recently, the same research group (http://www.tcd.uni-konstanz.de/index.php) that developed PLANTS docking software has launched SPORES to automatically perform proteins and ligands preparations before being submitted to PLANTS to undergo molecular docking simulations [18]. Previously, Yuniarti et al [6] and Hayun et al [8] employed MarvinSketch (http://www.chemaxon.com/products/ marvin/marvinsketch/) [23] and YASARA (http://www.yasara.org/) [24] to perform the preparations manually which need some careful checking to avoid error according to the incompatibility atom types with PLANTS.…”

“…Structure Protonation and Recognition System (SPORES) software (http://www.tcd.unikonstanz.de/research/spores.php), which assigns atom and bond type according to TRIPOS force field convention [18] was employed to virtually prepare the COX-1 structure as the protein target in the docking simulations using PLANTS. Together with Open Babel version 2.2.3 (http://openbabel.org/) [19], which employs Monte Carlo search with MMFF94 as the force field, SPORES was also used to prepare the ligand to be docked using PLANTS1.2.…”

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“…Moreover, the EF1% value of the validated protocol constructed here is significantly higher than the average value (17.3) resulted from the first SBVS campaign of 40 targets employing DUD and can therefore be considered as acceptable [10]. The validated protocol was subsequently employed to virtually screen eugenol (compound 1), its analogues (compounds 2-7) and their dimers (8)(9)(10)(11)(12)(13)(14). None of the compounds show better docking score as compared to the threshold compound of the EF1% value.…”

Molecular docking approach to identify potential anticancer compounds from Begonia (Begonia sp)

“…Open Babel version 2.2.3 (www.openbabel.org), employing Monte Carlo search with a force field of MMFF94 was used to virtually prepare the EFGR protein target and ligand, together with Structure Protonation and Recognition System (SPORES) software (www.tcd.unikonstanz.de/research/spores.php) [14][15]. Molecular docking simulation was subsequently performed by PLANTS1.2 [16].…”