Optimization of an in Silico Protocol Using Probe Permeabilities to Identify Membrane Pan-Assay Interference Compounds,Journal of Chemical Information and Modeling

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Optimization of an in Silico Protocol Using Probe Permeabilities to Identify Membrane Pan-Assay Interference Compounds
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-06-13 , DOI: 10.1021/acs.jcim.2c00372
Pedro R Magalhães ₁ , Pedro B P S Reis ₁ , Diogo Vila-Viçosa ₁ , Miguel Machuqueiro ₁ , Bruno L Victor ₁

Affiliation

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 in silico 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 in silico protocol that can be adopted as a future reference method to identify membrane PAINS.

中文翻译：

使用探针渗透性来优化计算机实验方案以识别膜泛检测干扰化合物

膜泛测定干扰化合物 (PAINS) 是一类与脂质双层非特异性相互作用并改变其理化性质的分子。及早鉴定这些化合物可以避免在药物发现活动中追寻虚假线索以及不必要的时间和资源浪费。在这项工作中，我们在伞式采样 (US)/分子动力学 (MD) 模拟的基础上优化了计算机实验方案，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盐原子可以减轻这种波动。在我们的美国方案中，通过减少雨伞的数量并调整其强度和位置，计算效率进一步提高。用于计算膜渗透系数的不均匀溶解度扩散模型（ISDM）证实了白藜芦醇和姜黄素具有不同的膜PAINS特征，并表明在先前的工作中对nothofagin的分类错误。总的来说，我们在这里提出了一种有前途的计算机协议，可以作为未来识别膜疼痛的参考方法。

更新日期：2022-06-13

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