Dataset Information

CSAlign and CSAlign-Dock: Structure alignment of ligands considering full flexibility and application to protein-ligand docking.

ABSTRACT: Structure prediction of protein-ligand complexes, called protein-ligand docking, is a critical computational technique that can be used to understand the underlying principle behind the protein functions at the atomic level and to design new molecules regulating the functions. Protein-ligand docking methods have been employed in structure-based drug discovery for hit discovery and lead optimization. One of the important technical challenges in protein-ligand docking is to account for protein conformational changes induced by ligand binding. A small change such as a single side-chain rotation upon ligand binding can hinder accurate docking. Here we report an increase in docking performance achieved by structure alignment to known complex structures. First, a fully flexible compound-to-compound alignment method CSAlign is developed by global optimization of a shape score. Next, the alignment method is combined with a docking algorithm to dock a new ligand to a target protein when a reference protein-ligand complex structure is available. This alignment-based docking method, called CSAlign-Dock, showed superior performance to ab initio docking methods in cross-docking benchmark tests. Both CSAlign and CSAlign-Dock are freely available as a web server at https://galaxy.seoklab.org/csalign.

SUBMITTER: Kwon S

PROVIDER: S-EPMC9719078 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

CSAlign and CSAlign-Dock: Structure alignment of ligands considering full flexibility and application to protein-ligand docking.

Kwon Sohee S Seok Chaok C

Computational and structural biotechnology journal 20221126

Structure prediction of protein-ligand complexes, called protein-ligand docking, is a critical computational technique that can be used to understand the underlying principle behind the protein functions at the atomic level and to design new molecules regulating the functions. Protein-ligand docking methods have been employed in structure-based drug discovery for hit discovery and lead optimization. One of the important technical challenges in protein-ligand docking is to account for protein con ...[more]

PMID: 36514334

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Project description:A database consisting of 780 ligand-receptor complexes, termed SB2010, has been derived from the Protein Databank to evaluate the accuracy of docking protocols for regenerating bound ligand conformations. The goal is to provide easily accessible community resources for development of improved procedures to aid virtual screening for ligands with a wide range of flexibilities. Three core experiments using the program DOCK, which employ rigid (RGD), fixed anchor (FAD), and flexible (FLX) protocols, were used to gauge performance by several different metrics: (1) global results, (2) ligand flexibility, (3) protein family, and (4) cross-docking. Global spectrum plots of successes and failures vs rmsd reveal well-defined inflection regions, which suggest the commonly used 2 Å criteria is a reasonable choice for defining success. Across all 780 systems, success tracks with the relative difficulty of the calculations: RGD (82.3%) > FAD (78.1%) > FLX (63.8%). In general, failures due to scoring strongly outweigh those due to sampling. Subsets of SB2010 grouped by ligand flexibility (7-or-less, 8-to-15, and 15-plus rotatable bonds) reveal that success degrades linearly for FAD and FLX protocols, in contrast to RGD, which remains constant. Despite the challenges associated with FLX anchor orientation and on-the-fly flexible growth, success rates for the 7-or-less (74.5%) and, in particular, the 8-to-15 (55.2%) subset are encouraging. Poorer results for the very flexible 15-plus set (39.3%) indicate substantial room for improvement. Family-based success appears largely independent of ligand flexibility, suggesting a strong dependence on the binding site environment. For example, zinc-containing proteins are generally problematic, despite moderately flexible ligands. Finally, representative cross-docking examples, for carbonic anhydrase, thermolysin, and neuraminidase families, show the utility of family-based analysis for rapid identification of particularly good or bad docking trends, and the type of failures involved (scoring/sampling), which will likely be of interest to researchers making specific receptor choices for virtual screening. SB2010 is available for download at http://rizzolab.org .

Dataset Information

CSAlign and CSAlign-Dock: Structure alignment of ligands considering full flexibility and application to protein-ligand docking.

Publications

CSAlign and CSAlign-Dock: Structure alignment of ligands considering full flexibility and application to protein-ligand docking.

Similar Datasets

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