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J Comput Aided Mol Des. 2017 May;31(5):419-439. doi: 10.1007/s10822-017-0015-8. Epub 2017 Mar 13.

ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs.

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA.
2
Dept. of Bioengineering and Therapeutic Sciences, University of California, San Francisco, USA. ajain@jainlab.org.

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.

PMID:
28289981
PMCID:
PMC5429375
DOI:
10.1007/s10822-017-0015-8
[Indexed for MEDLINE]
Free PMC Article

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