SOLUTION OF THE CONFORMATION AND ALIGNMENT TENSORS FOR THE BINDING OFTRIMETHOPRIM AND ITS ANALOGS TO DIHYDROFOLATE-REDUCTASE - 3D-QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDY USING MOLECULAR SHAPE-ANALYSIS, 3-WAY PARTIAL LEAST-SQUARES REGRESSION, AND 3-WAY FACTOR-ANALYSIS

Molecular recognition is the basis of rational drug design, and for th is reason it has been extensively studied. However, the process by whi ch a ligand recognizes and binds to its receptor is complex and not we ll understood. For the case in which the geometries (conformation and alignment) of the ligand and receptor are known from X-ray crystal str ucture data, the problem is simplified. The receptor-bound conformatio n and alignment of the ligand is assumed, and those of additional liga nds are inferred. For the general case in which the geometries of the ligand(s) and receptor are unknown, no general treatment or solution i s available and receptor-ligand geometries must be obtained indirectly from structure-activity studies or synthesis and evaluation of rigid analogs. A general treatment for solving for the receptor-bound geomet ry of a series of ligands is presented here. Using molecular shape ana lysis, for ligand description, tensor analysis of N-way arrays by part ial least-squares (PLS) regression, and 3-way factor analysis, the rec eptor-bound geometries of trimethoprim and a series of trimethoprim-li ke dihydrofolate reductase inhibitors are correctly predicted.