ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs.
ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs.
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DOI：
10.1007/s10822-017-0015-8
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发表时间：
2017-05
影响因子：
3.5
通讯作者：
Jain AN
中科院分区：
文献类型：
--
作者：
Cleves AE;Jain AN
我们介绍了ForceGen方法的3D结构生成和构象的药物样小分子的阐述。ForceGen是新颖的，避免了使用距离几何，分子模板，或面向模拟的随机采样。该方法主要由分子力场驱动，使用MMFF 94的扩展和基于电负性均衡的部分电荷估计器来实现。力场耦合到算法，用于对小分子所做的真实物理运动进行直接采样。结果是在来自剑桥晶体数据库的480个药物样小分子的标准基准上呈现的，包括来自SMILES字符串的完整结构生成。在四个精心策划的数据集上证明了蛋白质结合的晶体学配体姿势的再现：ConfGen集（667个配体），PINC交叉对接基准（1062个配体），大环配体的大集合（182个，典型的环尺寸为12-23个原子），以及用于评估大环构象生成的常用基准（30个配体）。结果与替代方法相比有利，并且对大环化合物的性能接近在非大环化合物上观察到的性能，同时产生比具有可比性能的基于MD的替代方法大约100倍的速度改进。
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.