Journal of Computer-Aided Molecular Design

, Volume 15, Issue 7, pp 613–647

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

  • Sung-Sau So
  • Martin Karplus

DOI: 10.1023/A:1011945119287

Cite this article as:
So, SS. & Karplus, M. J Comput Aided Mol Des (2001) 15: 613. doi:10.1023/A:1011945119287


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 predictionglycogen phosphorylase inhibitorLUDIMCSSQSARstructure-based drug design

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Sung-Sau So
    • 1
  • Martin Karplus
    • 1
    • 2
  1. 1.Department of Chemistry and Chemical BiologyHarvard UniversityCambridgeU.S.A
  2. 2.Laboratoire de Chimie Biophysique, Institut le BelUniversité Louis PasteurStrasbourgFrance