Journal of Computer-Aided Molecular Design

, Volume 15, Issue 7, pp 613-647

First online:

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

  • Sung-Sau SoAffiliated withDepartment of Chemistry and Chemical Biology, Harvard University
  • , Martin KarplusAffiliated withDepartment of Chemistry and Chemical Biology, Harvard UniversityLaboratoire de Chimie Biophysique, Institut le Bel, Université Louis Pasteur

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Glycogen phosphorylase (GP) is an important enzyme that regulates blood glucose level and a key therapeutic target for the treatment of type II diabetes. 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 existing lead molecules; the use of 2D and 3D similarity-based QSAR models (HQSAR and SMGNN) and of the LUDI program to identify novel molecules that may bind to the glucose binding site. The designed ligands are evaluated by a multiple screening method, which is a combination of commercial and in-house ligand-receptor binding affinity prediction programs used in a previous study (So and Karplus, J. Comp.-Aid. Mol. Des., 13 (1999), 243–258). Each method is used at an appropriate point in the screening, as determined by both the accuracy of the calculations and the computational cost. A comparison of the strengths and weaknesses of the ligand design approaches is made.

binding affinity prediction glycogen phosphorylase inhibitor LUDI MCSS QSAR structure-based drug design