DG-AMMOS: A New tool to generate 3D conformation of small molecules using Distance Geometry and Automated MolecularMechanics Optimization for in silico Screening

摘要

Background: Discovery of new bioactive molecules that could enter drug discovery programs orthat could serve as chemical probes is a very complex and costly endeavor. Structure-based andligand-based in silico screening approaches are nowadays extensively used to complementexperimental screening approaches in order to increase the effectiveness of the process andfacilitating the screening of thousands or millions of small molecules against a biomolecular target.Both in silico screening methods require as input a suitable chemical compound collection and mostoften the 3D structure of the small molecules has to be generated since compounds are usuallydelivered in 1D SMILES, CANSMILES or in 2D SDF formats.Results: Here, we describe the new open source program DG-AMMOS which allows thegeneration of the 3D conformation of small molecules using Distance Geometry and their energyminimization via Automated Molecular Mechanics Optimization. The program is validated on theAstex dataset, the ChemBridge Diversity database and on a number of small molecules with knowncrystal structures extracted from the Cambridge Structural Database. A comparison with the freeprogram Balloon and the well-known commercial program Omega generating the 3D of smallmolecules is carried out. The results show that the new free program DG-AMMOS is a veryefficient 3D structure generator engine.Conclusion: DG-AMMOS provides fast, automated and reliable access to the generation of 3Dconformation of small molecules and facilitates the preparation of a compound collection prior tohigh-throughput virtual screening computations. The validation of DG-AMMOS on several differentdatasets proves that generated structures are generally of equal quality or sometimes better thanstructures obtained by other tested methods.