Conceptual Prediction of Drug Bioactivities in Cell-Based Assays: cell-QSAR

描述（由申请人提供）：如果受体是未知的、可分离的或分离后具有功能的，则基于细胞的筛选已用于药物开发；或者寻求细胞水平的反应。未解决的药物处置和受体结合对测量效应的贡献阻碍了铅结构的优化。如果缓慢的运输和/或与非受体细胞成分的相互作用阻碍了受体周围有效药物浓度的达到，那么有价值的配体在细胞检测中就不会被注意到。为了解释细胞数据解释的复杂因素，我们将开发一种基于结构的计算工具，称为处置函数（DF），用于估计细胞内药物处置的动力学。为了使DF尽可能通用和实用，将使用替代系统中测量的药物特性来描述被动运输过程中的构象平均相互作用，并通过三维定量构效关系（3D-QSAR）表达与大分子的构象特异性结合。在哺乳动物中，由50%以上的磷脂酰胆碱（PC）组成的磷脂双分子层的积累包括两种不同类型的溶剂化-在核心和在头群区域。虽然十六烷（C16）是一个很好的替代溶剂的核心，药物溶剂化的头基团区域，占据约三分之一的双层体积，是不清楚的。一种新的替代溶剂，二乙酰-PC （DAcPC，即具有截断脂肪酸链的PC头基），水合到流体双分子层的典型程度，将用于测量数百种药物的头基类溶剂化能。对于所有常见的药物片段，将DAcPC和C16溶剂化能解卷积成片段贡献，并使用与双层数据的概念相关性来调整以表示实验头群和核心量。我们假设，为了获得最大的跨双层运输速率，药物必须对头基团、核心和它们之间的界面表现出中间的相互作用亲和力。基于这一假设，实验输运动力学数据将在概念上与头基团和核心溶剂化能相关联，以获得DF的基线形式，仅使用脂质和蛋白质含量来估计细胞系统的药物处置。基线DF将用于代表性的G+和G-细菌，以及使用摄取数据和概念3D-QSAR与惰性蛋白的构象特异性结合的两种人类细胞系。DFs将与目前基于配体和基于受体的QSAR技术相结合，为分离的受体数据开发，以提供适合处理细胞水平生物活性的细胞QSAR模型。校准后的细胞- qsar模型可以被其他人用作软件或web服务，从细胞分析数据中提取受体亲和力，针对处置和受体结合单独优化药物结构，将良好的粘合剂转化为有希望的候选药物，在系统生物学模型中描述药物处置，并通过估计双层区域和细胞内处置的积累来注释PubChem和其他数据库中的药物结构。

DESCRIPTION (provided by applicant): Cell-based screening has been used in drug development, if the receptors are either not known, isolable, or functional upon isolation; or if cell-level responses are sought. Unresolved contributions of the drug disposition and receptor binding to the measured effects hamper lead structure optimization. Valuable ligands pass unnoticed through cellular assays, if slow transport and/or interactions with non-receptor cell constituents prevent the attainment of the effective drug concentration in the receptor surroundings. To account for the factors complicating the interpretation of cellular data, we will develop a structure-based computational tool, called the disposition function (DF), estimating the kinetics of intracellular drug disposition. To make the DF as general and practical as possible, conformation-averaged interactions during passive transport will be described using drug properties measured in surrogate systems, and conformation-specific binding to macromolecules will be expressed via 3-dimensional quantitative structure-activity relationships (3D-QSAR). Accumulation in phospholipid bilayers, composed of more than 50% phosphatidylcholine (PC) in mammals, comprises two distinct types of solvation - in the core and in the headgroup region. While hexadecane (C16) is a good surrogate solvent for the core, drug solvation in the headgroup regions, occupying about a third of the bilayer volume, is not understood properly. A novel surrogate solvent, diacetyl-PC (DAcPC, i.e. the PC headgroup with the truncated fatty acid chains), hydrated to the extent typical for a fluid bilayer, will be used to measure the headgroup-like solvation energies of hundreds of drugs. For all common drug fragments, the DAcPC and C16 solvation energies will be deconvoluted into fragment contributions, and adjusted to express the experimental headgroup and core quantities using conceptual correlations with the bilayer data. We hypothesize that for the maximum trans-bilayer transport rates, drugs must exhibit intermediate interaction affinities for the headgroups, core, and the interface between them. Based on this hypothesis, experimental transport kinetics data will be conceptually correlated with the headgroup and core solvation energies, to obtain a baseline form of the DF that estimates drug disposition for cellular systems, using just the lipid and protein contents. The baseline DF will be refined for representative G+ and G- bacteria, and two human cell lines using the uptake data and conceptual 3D-QSAR for conformation-specific binding to inert proteins. The DFs will be combined with current ligand-based and receptor-based QSAR techniques, developed for isolated receptor data, to provide cell-QSAR models suitable for processing cell-level bioactivities. The calibrated cell-QSAR models can be utilized by others as software or a web service to extract receptor affinities from cell-assay data, optimize drug structures individually for disposition and receptor binding, convert good binders to promising drug candidates, describe drug disposition in systems biology models, and annotate drug structures in PubChem and other databases by the estimates of accumulation in bilayer regions and intracellular disposition. PUBLIC HEALTH RELEVANCE: For many drugs, transport into the cells is one of the key processes for the therapeutic effect. The planned research will find out, how the rate and extent of the cellular entry depend on molecular structure and physicochemical properties of drug candidates. This information will be used do create software and a web service that will help other scientists to develop better and safer drugs faster.