Hiệu ứng sinh học được trung gian bởi các tương tác giữa các phân tử, ví dụ, thông qua các ràng buộc của một phối tử với một thụ thể, kích hoạt một sự kiện truyền tín hiệu trong một con đường truyền tín hiệu. Cấu trúc ba chiều (3D) của khu phức hợp receptor-ligand được giá trị tuyệt vời để hợp lý hóa các tác dụng dược lý hoặc độc tính của các phối tử phân tử nhỏ. Tuy nhiên, do hạn chế thử nghiệm như độ tinh khiết và tính đồng nhất của protein, crystallizability, tính hòa tan,. | 2 Description and Representation of Chemicals WOLFGANG GUBA F. Hoffmann-La Roche Ltd Pharmaceuticals Division Basel Switzerland 1. INTRODUCTION Biological effects are mediated by intermolecular interactions for instance through the binding of a ligand to a receptor which triggers a signaling event in a signal transduction pathway. Three-dimensional 3D structures of receptor-ligand complexes are of great value to rationalize pharmacological or toxicological effects of small molecule ligands. However due to experimental constraints such as purity and homogeneity of the protein crystallizability solubility size of the protein-ligand complex etc. an X-ray or NMR-based structure determination is often not feasible. In those cases empirical models have to be developed that deduce biological effects 11 2005 by Taylor Francis Group LLC 12 Guba from the 2D or 3D molecular structures of small molecule ligands only and as a result structure-activity relationships SAR are formulated. These SARs may either be qualitative . molecular features substructures functional groups are associated with activity or quantitative SARs QSARs defined by correlating molecular structures with biological effects via mathematical equations . QSAR models require the translation of molecular structures into numerical scales . molecular descriptors. These descriptors are used by various linear partial least squares PLS 1 etc. or non-linear neural networks 2 regression algorithms to predict biological effects of molecules which have not been tested or not even synthesized. The core of empirical model building by QSAR is the similarity principle 3 which states that similar chemical structures should have similar biological activities. The converse is not true since similar biological activities may be displayed by chemically diverse molecules 4 . Within the context of QSAR the similarity principle implies that small changes in molecular structure cause correspondingly slight variations in .
