Rational design is a promising approach because it provides a tool that allows screening of far fewer compounds, reducing many thousands to hundreds. It is particularly useful, Dr. Cooper added, for kinases, nuclear hormone receptors, soluble enzymes, and certain ion-channel targets where one might develop structure activity relationships through structure-based design aimed at specific molecular binding sites for a given target of interest.
In a presentation on the use of rational design, “Recent Advances in Structure-Based Lead Optimization,” Woody Sherman, director of applications science at Schrodinger (www.schrodinger.com), presented improvements in lead optimization using the Schrodinger software suite.
“Crystal structures provide a great way to better understand how small molecules interact with the target of interest to increase binding strength or target specificity, whether with proteins, DNA, RNA, or glycoproteins. When crystal structures are not available, the group can build homology models or create induced-fit models,” Sherman noted.
Schrodinger’s Induced-fit Docking (IFD) methodology was developed to address situations in which it is important to account for protein flexibility and provides a computational surrogate to generate quite accurate models of protein-ligand complexes, he said. The iterative procedure combines flexible ligand docking and protein structure refinement.
“Even in cases of docking similar molecules, accounting for induced-fit can be important in generating the correct protein-ligand complex structure. Without the right complex structure, one cannot hope to accurately predict ligand-binding affinities,” Sherman observed.
The quality of the results obtained in an iterative protocol like IFD is highly dependent on the quality of the programs used, Sherman said, with factors such as the force field and sampling algorithm playing important roles. “It is not enough to just combine any programs for docking and protein refinement without performing the right validation. It is important to get the science right and combine methods in an intelligent way,” said Sherman.
“Once we obtain an accurate receptor-ligand complex, we use Prime MM-GBSA to rank order the binding of molecules within a congeneric series, as is necessary in lead-optimization projects.”
The software emphasizes using an accurate forcefield and solvation model. Additionally, the method now can use quantum mechanical charges directly in the calculation. Finally, Sherman discussed the use of MCPRO+, released last month, which uses Monte Carlo statistical mechanics simulations to compute free-energy changes between molecules via Free Energy Perturbation (FEP) calculations.
“MCPRO was developed by Bill Jorgensen at Yale,” Sherman said. “Schrodinger has kept the rigorous scientific methods in place while simplifying the interface to make FEP calculations accessible to nonexperts. The integration of these tools and other advances in the Schrodinger software suite is making lead optimization by computational approaches more feasible and successful. We are seeing successes more frequently in real drug discovery projects.”