title: ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs.
abstract: We introduce the ForceGen method for 3D structure generation and conformer elaboration of drug-like small molecules. ForceGen is novel, avoiding use of distance geometry, molecular templates, or simulation-oriented stochastic sampling. The method is primarily driven by the molecular force field, implemented using an extension of MMFF94s and a partial charge estimator based on electronegativity-equalization. The force field is coupled to algorithms for direct sampling of realistic physical movements made by small molecules. Results are presented on a standard benchmark from the Cambridge Crystallographic Database of 480 drug-like small molecules, including full structure generation from SMILES strings. Reproduction of protein-bound crystallographic ligand poses is demonstrated on four carefully curated data sets: the ConfGen Set (667 ligands), the PINC cross-docking benchmark (1062 ligands), a large set of macrocyclic ligands (182 total with typical ring sizes of 12-23 atoms), and a commonly used benchmark for evaluating macrocycle conformer generation (30 ligands total). Results compare favorably to alternative methods, and performance on macrocyclic compounds approaches that observed on non-macrocycles while yielding a roughly 100-fold speed improvement over alternative MD-based methods with comparable performance.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Cleves
authors.affiliation: Dept. of Bioengineering and Therapeutic Sciences, University of California, San Francisco, USA. ajain@jainlab.org.
authors.forename: Ajay N
authors.initials: AN
authors.lastname: Jain
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D062126:Databases, Chemical; D006801:Humans; D008024:Ligands; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047028:Macrocyclic Compounds