Frog2: Efficient 3D conformation ensemble generator for small compounds

Abstract

Frog is a web tool dedicated to small compound 3D generation. Here we present the new version, Frog2, which allows the generation of conformation ensembles of small molecules starting from either 1D, 2D or 3D description of the compounds. From a compound description in one of the SMILES, SDF or mol2 formats, the server will return an ensemble of diverse conformers generated using a two stage Monte Carlo approach in the dihedral space. When starting from 1D or 2D description of compounds, Frog2 is capable to detect the sites of ambiguous stereoisomery, and thus to sample different stereoisomers. Frog2 also embeds new energy minimization and ring generation facilities that solve the problem of some missing cycle structures in the Frog1 ring library. Finally, the optimized generator of conformation ensembles in Frog2 results in a gain of computational time permitting Frog2 to be up to 20 times faster that Frog1, while producing satisfactory conformations in terms of structural quality and conformational diversity. The high speed and the good quality of generated conformational ensembles makes it possible the treatment of larger compound collections using Frog2. The server and documentation are freely available at http://bioserv.rpbs.univ-paris-diderot.fr/Frog2.

Figure 1.

Flowchart of Frog2.

Figure 2.

RMSD between the best-fitted conformers and the X-ray structures for conformers generated by: (a) Frog1 versus Frog2 for series of up to 50 conformers; (b) Frog2 versus Omega for series of up to 50 conformers. PDB codes denote (i) the compounds with poorest relative performance, i.e. deviating the most from the diagonal (1y6b, 1xoz) and (ii) best performing for both Frog2 and Omega (1gpk, 1u4d, 1sqn); and (c) Frog2 for series of up to 50 conformers versus Frog2 for series of up to 100 conformers.

Figure 3.

Conformational ensembles for two small molecules of the Astex dataset generated by Frog2 (all atom colors, carbons in yellow) and Omega (all atom colors, carbons in light pink: (a) PDB code 1jla; and (b) PDB code 1meh. The experimental structure of the co-crystallized ligands are also shown (all atom colors, carbons in magenta).