FITTED 2.2: A Docking-based Virtual Screening Software Program for Drug Discovery

FITTED 2.2 is a suite of programs to dock flexible ligands into flexible proteins. This software relies on a genetic algorithm to account for flexibility of the two molecules and location of water molecules, and on a novel application of a switching function to retain or displace water molecules and to form potential covalent bonds with the protein side-chains.

An integral part of the drug discovery process is to in silico screen libraries (virtual screening) of compounds in order to prioritize compounds for biochemical assays and, most importantly, to introduce rationale in the selection process. Presently, almost all the docking protocols used are based on a rigid receptor model and do not take into account the mobility of the ensemble of amino acids that constitute the binding site of the ligand.FITTED 2.2 aims at improving the accuracy of existing molecule docking software program. It uses a more accurate protein models and is based on a pharmacophore-oriented docking method combined with a genetic algorithm based docking approach. The later takes advantage of more than one structure to dock compounds in virtually flexible proteins. A library of experimentally observed protein conformations is used and composite structures are created in order to model the protein flexibility and to explore a wide region of conformational space. The proteins, ligands and potential bridging water molecules are described as genes and a mixed Lamarckian/Darwinian evolution optimizes the whole complex. BENEFITS: Accuracy: a significant increase in the accuracy of the virtual docking process is observed. Speed: aspects of the program that are common to all runs are performed only once.

Successful and accurate docking of various enzyme inhibitors (i.e., HIV-1 protease, trypsin, MMPs, mannosidase), receptor agonists and antagonists (glutamate receptor) and virtual screening of enzyme inhibitors (i.e., CDK2, thymidine kinase, HCV polymerase) receptor agonists and antagonists (estrogen receptor).