The Development of Models Based on Linear and Nonlinear Multivariate Methods to Predict ADME/PK Properties Using Physicochemical Properties of Kinase, Protease Inhibitors, and GPCR Antagonists

Oral bioavailability of a drug compound is the significant property for potential drug candidates. Measuring this property can be costly and time-consuming. Quantitative structure-property relationships (QSPRs) are used to estimate the percentage of oral bioavailability, and they are an attractive alternative to experimental measurements. A data set of 217 drug and drug-like compounds with measured values of the percentage of oral bioavailability taken from the small molecule ChemBioBase database was used to develop and test a QSPR model. Descriptors were calculated for the compounds using Codessa 2.1 tool. Nonlinear general regression neural network model was generated using the DTREG predictive modeling program software. The calculated percentage of oral bioavailability model performs well, with root-mean-square (rms) errors of 4.55% oral bioavailability units for the training set, 14.32% oral bioavailability units for the test set, and 19.12% oral bioavailability units for the external prediction set. Given the structural diversity and bias of the data set, this is a good first attempt at modeling oral bioavailability using QSPR methods. The model can be used as a potential virtual screen or property estimator. With a larger data supply less biased toward the high end values of the percentage of oral bioavailability, a more successful model could likely be developed. 1. Introduction Rational drug discovery requires early methods of all factors influencing on the likely success of a drug candidate in the subsequent stages of the drug development. The study of absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME/PK) has become a major discipline in drug discovery through the application of well-established in vitro and in vivo methodologies [1]. PK plays a crucial role in the pharmaceutical research and development and, because of the major role of drug metabolism, drug discovery research in this area is covered by groups coalesced around the name drug metabolism and pharmacokinetics (DMPKs) [2–6]. Elimination is the product of metabolism and excretion. Pharmacokinetics describe how the body reacts to a specific drug after administration. Pharmacokinetic properties of drugs may be affected by factors such as the administration site and the administered drug dose; these may influence the rate of absorption. One more process, liberation, plays an important role in pharmacokinetics: liberation means the release of drug from the formulation [7]. The primary goal of the drug discovery and development process is to find a molecule