FLOG - A SYSTEM TO SELECT QUASI-FLEXIBLE LIGANDS COMPLEMENTARY TO A RECEPTOR OF KNOWN 3-DIMENSIONAL STRUCTURE

We present a system, FLOG (Flexible Ligands Oriented on Grid), that se arches a database of 3D coordinates to find molecules complementary to a macromolecular receptor of known 3D structure. The philosophy of FL OG is similar to that reported for DOCK [Shoichet, B.K. et al., J. Com put. Chem., 13 (1992) 380]. In common with that system, we use a match center representation of the volume of the binding cavity and we use a clique-finding algorithm to generate trial orientations of each cand idate ligand in the binding site. Also we use a grid representation of the receptor to assess the fit of each orientation. We have introduce d a number of novel features within this paradigm. First, we address l igand flexibility by including up to 25 explicit conformations of each structure in our databases. Nonhydrogen atoms in each database entry are assigned one of seven atom types (anion, cation, donor, acceptor, polar, hydrophobic and other) based on their local bonded chemical env ironments. Second, we have devised a new grid-based scoring function c ompatible with this 'heavy atom' representation of the ligands. This i ncludes several potentials (electrostatic, hydrogen bonding, hydrophob ic and van der Waals) calculated from the location of the receptor ato ms. Third, we have improved the fitting stage of the search. Initial d ockings are generated with a more efficient clique-finding algorithm. This new algorithm includes the concept of 'essential points', match c enters that must be paired with a ligand atom. Also, we introduce the use of a rapid simplex-based rigid-body optimizer to refine the orient ations. We demonstrate, using dihydrofolate reductase as a sample rece ptor, that the FLOG system can select known inhibitors from a large da tabase of drug-like compounds.