a Department of Bioinformatics, Applied Botany Centre (ABC), University School of Sciences , Gujarat University , Ahmedabad , India.
b Molecular Biophysics Unit , Indian Institute of Science , Bangalore , India.
Toxicol Mech Methods. 2018 Nov;28(9):685-698. doi: 10.1080/15376516.2018.1499840. Epub 2018 Sep 27.
Structure-based models to understand the transport of small molecules through biological membrane can be developed by enumerating intermolecular interactions of the small molecule with a biological membrane, usually a dimyristoylphosphatidylcholine (DMPC) monolayer. This ADME (absorption, distribution, metabolism, and excretion) property based on Madin-Darby Canine Kidney (MDCK) cell line demonstrates intestinal drug absorption of small molecules and correlated to human intestinal absorption which acts as a determining factor to forecast small-molecule prioritization in drug-discovery projects. We present here the development of MDCKpred web-tool which calculates MDCK permeability coefficient of small molecule based on the regression model, developed using membrane-interaction chemical features. The web-tool allows users to calculate the MDCK permeability coefficient (nm/s) instantly by providing simple descriptor inputs. The chemical-interaction features are derived from different parts of the DMPC molecule viz. head, middle, and tail regions and accounts overall intermolecular contacts of the small molecule when passively diffused through the phospholipid-rich biological membrane. The MDCKpred model is both internally (R = .76; [Formula: see text]= .68; R = .87; R = .69) and externally (R = .55) validated. Furthermore, we used natural molecules as application examples to demonstrate its utility in lead exploration and optimization projects. The MDCKpred web-tool can be accessed freely at http://www.mdckpred.in . This web-tool is designed to offer an intuitive way of prioritizing small molecules based on calculated MDCK permeabilities.
基于结构的模型可用于研究小分子通过生物膜的传输，此类模型通过列举小分子与生物膜（通常为二肉豆蔻酰磷脂酰胆碱（DMPC）单层）之间的分子间相互作用来构建。该基于 Madin-Darby Canine Kidney（MDCK）细胞系的 ADME（吸收、分布、代谢和排泄）特性可用于预测小分子的肠道药物吸收，与人类肠道吸收相关联，后者是预测小分子在药物发现项目中的优先级的决定因素。我们在此介绍了 MDCKpred 网络工具的开发，该工具可根据膜相互作用化学特征开发的回归模型来计算小分子的 MDCK 渗透率系数。该网络工具允许用户通过提供简单的描述符输入来即时计算 MDCK 渗透率系数（nm/s）。化学相互作用特征源自 DMPC 分子的不同部分，例如头部、中部和尾部区域，并在小分子被动扩散通过富含磷脂的生物膜时计算小分子的总分子间接触。MDCKpred 模型具有内部（R =.76；[公式：见正文] =.68；R =.87；R =.69）和外部（R =.55）验证。此外，我们使用天然分子作为应用示例来证明其在探索和优化先导化合物项目中的实用性。该 MDCKpred 网络工具可在 http://www.mdckpred.in 免费访问。该网络工具旨在提供一种基于计算出的 MDCK 渗透率来对小分子进行优先级排序的直观方法。
