A Priori Prediction of Tissue: Plasma Partition Coefficients (Log BP) of Drugs to Facilitate the Use of MLR and MLR-GA Methods

Abstract

It is important to determine whether a candidate molecule is capable of penetrating the plasma-brain barrier in<br />drug discovery and development. The aim of this paper is to establish a predictive model for plasma-brain<br />barrier penetration using simple descriptors The usefulness of the quantum chemical descriptors, calculated at<br />the level of the DFT and HE theories using 6-310* basis set for QSAR study of anti-vial Nucleoside<br />Analogues drugs was examined. Delivery of anti-viral agents into the central nervous system (CNS) is clmically<br />hoportant. Nucleoside analogues are a major source of clinically used antiviral agents. The QSAR model<br />developed contributed to a mechanistic understanding of the investigated biological effects. The first step in this<br />study was to use a dauset containing 23 drugs with known activity. In the next steps some of them with the<br />large secondary chain branches were removed to make our approach. Multiple Linear Regressions (MLR) was<br />employed to model the relationships between molecular descriptors and biological activities of molecules using<br />stepwise method and genetic algorithm as variable selection tools. Biological activities contain the logarithm of<br />the ratio of the steady-state concentration of a compound in the brain to in the plasma, log Bp. A multiparametric<br />equation containing maximum six descriptors at HF/6-3 10* and eight descriptors at 133LYP/6-3 10*<br />method with good statistical qualities<br />(Rpax— 0.976 , 11214n— 0.959 at HF/6-3/G* and Rwax4 0.979 , 112KGP 0.952 at B3LYP/6-316*) was<br />btiledbyMl(plLR gr g teP thoi Th Sal d d ibis p pe ppears to be<br />very simple but robust and effective for predictive use This method relates log Bp values to fundamental<br />molecular properties, such as Electrostatic Potential. Local charge, Electric Field Gradient, Isotropic<br />parameters, Natural Population Analysis. Also, GA-MLR regression was used to model the structure — activity<br />relationships.