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Protein Flexibility in Ligand Docking and Virtual Screening to Protein Kinases

Summary: Protein Flexibility in Ligand Docking and Virtual
Screening to Protein Kinases
Claudio N. Cavasotto* and Ruben A. Abagyan
Molsoft LLC, 3366 N Torrey
Pines Ct. Suite 300, La Jolla
CA 92037, USA
The main complicating factor in structure-based drug design is receptor
rearrangement upon ligand binding (induced fit). It is the induced fit
that complicates cross-docking of ligands from different ligand­receptor
complexes. Previous studies have shown the necessity to include protein
flexibility in ligand docking and virtual screening. Very few docking
methods have been developed to predict the induced fit reliably and, at
the same time, to improve on discriminating between binders and non-
binders in the virtual screening process.
We present an algorithm called the ICM-flexible receptor docking algor-
ithm (IFREDA) to account for protein flexibility in virtual screening. By
docking flexible ligands to a flexible receptor, IFREDA generates a discrete
set of receptor conformations, which are then used to perform flexible
ligand­rigid receptor docking and scoring. This is followed by a merging
and shrinking step, where the results of the multiple virtual screenings are


Source: Abagyan, Ruben - School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego


Collections: Biology and Medicine