BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal.
J Chem Inf Model. 2022 Jun 27;62(12):3034-3042. doi: 10.1021/acs.jcim.2c00372. Epub 2022 Jun 13.
Membrane pan-assay interference compounds (PAINS) are a class of molecules that interact nonspecifically with lipid bilayers and alter their physicochemical properties. An early identification of these compounds avoids chasing false leads and the needless waste of time and resources in drug discovery campaigns. In this work, we optimized an protocol on the basis of umbrella sampling (US)/molecular dynamics (MD) simulations to discriminate between compounds with different membrane PAINS behavior. We showed that the method is quite sensitive to membrane thickness fluctuations, which was mitigated by changing the US reference position to the phosphate atoms of the closest interacting monolayer. The computational efficiency was improved further by decreasing the number of umbrellas and adjusting their strength and position in our US scheme. The inhomogeneous solubility-diffusion model (ISDM) used to calculate the membrane permeability coefficients confirmed that resveratrol and curcumin have distinct membrane PAINS characteristics and indicated a misclassification of nothofagin in a previous work. Overall, we have presented here a promising protocol that can be adopted as a future reference method to identify membrane PAINS.
膜泛分析干扰化合物（PAINS）是一类与脂双层非特异性相互作用并改变其物理化学性质的分子。早期识别这些化合物可以避免追逐虚假线索，并避免在药物发现活动中浪费时间和资源。在这项工作中，我们在伞状采样（US）/分子动力学（MD）模拟的基础上优化了一种方案，以区分具有不同膜 PAINS 行为的化合物。我们表明，该方法对膜厚度波动非常敏感，通过将 US 参考位置更改为最接近相互作用的单层的磷酸原子，可以减轻这种影响。通过减少伞的数量并调整其强度和位置，进一步提高了计算效率我们的 US 方案。用于计算膜渗透系数的非均匀溶解-扩散模型（ISDM）证实，白藜芦醇和姜黄素具有明显的膜 PAINS 特征，并表明在以前的工作中对 nothofagin 的分类错误。总的来说，我们在这里提出了一种很有前途的方案，可以作为未来识别膜 PAINS 的参考方法。
