Evaluation of designed ligands by a multiple screening method: Applicationto glycogen phosphorylase inhibitors constructed with a variety of approaches

Glycogen phosphorylase (GP) is an important enzyme that regulates blood glu cose level and a key therapeutic target for the treatment of type II diabet es. In this study, a number of potential GP inhibitors are designed with a variety of computational approaches. They include the applications of MCSS, LUDI and CoMFA to identify additional fragments that can be attached to ex isting lead molecules; the use of 2D and 3D similarity-based QSAR models (H QSAR and SMGNN) and of the LUDI program to identify novel molecules that ma y bind to the glucose binding site. The designed ligands are evaluated by a multiple screening method, which is a combination of commercial and in-hou se ligand-receptor binding affinity prediction programs used in a previous study (So and Karplus, J. Comp.-Aid. Mol. Des., 13 (1999), 243-258). Each m ethod is used at an appropriate point in the screening, as determined by bo th the accuracy of the calculations and the computational cost. A compariso n of the strengths and weaknesses of the ligand design approaches is made.