Computational & Structural Chemistry, Merck & Co Inc, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Bioengineering and Therapeutic Sciences, University of California San Francisco, Box 0128, San Francisco, California 94158, United States.
J Med Chem. 2021 Mar 25;64(6):3282-3298. doi: 10.1021/acs.jmedchem.0c02159. Epub 2021 Mar 16.
Macrocyclic peptides are an important modality in drug discovery, but molecular design is limited due to the complexity of their conformational landscape. To better understand conformational propensities, global strain energies were estimated for 156 protein-macrocyclic peptide cocrystal structures. Unexpectedly large strain energies were observed when the bound-state conformations were modeled with positional restraints. Instead, low-energy conformer ensembles were generated using xGen that fit experimental X-ray electron density maps and gave reasonable strain energy estimates. The ensembles featured significant conformational adjustments while still fitting the electron density as well or better than the original coordinates. Strain estimates suggest the interaction energy in protein-ligand complexes can offset a greater amount of strain for macrocyclic peptides than for small molecules and non-peptidic macrocycles. Across all molecular classes, the approximate upper bound on global strain energies had the same relationship with molecular size, and bound-state ensembles from xGen yielded favorable binding energy estimates.
大环肽是药物发现中的一种重要模式，但由于其构象景观的复杂性，分子设计受到限制。为了更好地理解构象倾向，我们对 156 个蛋白质-大环肽共晶结构的全局应变能进行了估计。当用位置约束模拟结合态构象时，观察到出乎意料的大应变能。相反，使用 xGen 生成了低能构象集合，这些集合符合实验 X 射线电子密度图，并给出了合理的应变能估计。这些集合在保持与电子密度拟合良好或更好的同时，表现出显著的构象调整。应变估计表明，在蛋白质-配体复合物中，相互作用能可以抵消大环肽比小分子和非肽大环更大的应变。在所有分子类别中，全局应变能的近似上限与分子大小具有相同的关系，并且 xGen 的结合态集合产生了有利的结合能估计。
