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Abstract

FLEXX-PHARM, an extended version of the flexible docking tool FLEXX, allows the incorporation of information about important characteristics of protein-ligand binding modes into a docking calculation. This information is introduced as a simple set of constraints derived from receptor-based type pharmacophore features. The constraints are determined by selected FLEXX interactions and inclusion volumes in the receptor active site. They guide the docking process to produce a set of docking solutions with particular properties. By applying a series of look-ahead checks during the flexible construction of ligand fragments within the active site, FLEXX-PHARM determines which partially built docking solutions can potentially obey the constraints. Solutions that will not obey the constraints are deleted as early as possible, often decreasing the calculation time and enabling new docking solutions to emerge. FLEXX-PHARM was evaluated on various individual protein-ligand complexes where the top docking solutions generated by FLEXX had high root mean square deviations (RMSD) from the experimentally observed binding modes. FLEXX-PHARM showed an improvement in the RMSD of the top solutions in most cases, along with a reduction in run time. We also tested FLEXX-PHARM as a database screening tool on a small dataset of molecules for three target proteins. In two cases, FLEXX-PHARM missed one or two of the active molecules due to the constraints selected. However, in general FLEXX-PHARM maintained or improved the enrichment shown with FLEXX, while completing the screen in considerably less run time.

Structure-Based Drug Design: Docking and Scoring

“…The advantage of this approach is twofold: speed through a rapid preorientation of the molecules to be docked as well as introducing bias towards good solutions by defining pharmacophore points that represent favorable interactions with the target binding site. The use of another docking program where one can apply pharmacophoric constraints during docking (FlexX-Pharm [116]) is illustrated below in the section on application examples.…”

“…In the next step the remaining compounds were evaluated by their fit to a pharmacophore representing a minimal kinase binding motif, consisting of two hydrogen bonds (one acceptor, one donor) with the hinge region of the kinase, where the adenine moiety of ATP binds. Approximately 200 000 compounds passed this pharmacophore filter and were subsequently submitted to docking with FlexX-Pharm [116] with the same pharmacophore as constraint. Up to 100 poses were saved for each successfully docked compound.…”

Virtual Screening and Its Integration with Modern Drug Design Technologies

“…4). The 3D pharmacophore queries are used to screen databases of compounds with the assistance of appropriate software, such as UNITY (Chemical Information Software, version 4.1, Tripos), Catalyst [47], or FlexX-Pharm [48], and only those molecules that carry the pharmacophoric features in the 3D space are retrieved and selected for the next VS steps.…”

Predicting Molecular Interactions in silico: I. A Guide to Pharmacophore Identification and its Applications to Drug Design

“…An example of a recently developed method is FlexX-Pharm [137]. This is an extended version of FlexX [138], which incorporates pharmacophore information.…”