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Journal of Computer-Aided Molecular Design

, Volume 31, Issue 5, pp 419–439

First Online: 13 March 2017Received: 09 February 2017Accepted: 27 February 2017DOI: 10.1007-s10822-017-0015-8

Cite this article as: Cleves, A.E. & Jain, A.N. J Comput Aided Mol Des 2017 31: 419. doi:10.1007-s10822-017-0015-8


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.

Autor: Ann E. Cleves - Ajay N. Jain


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