A molecular docking computer program (DOCK) was used to screen the Fine Chemical Directory, a database of commercially available compounds, for molecules that are complementary to thymidylate synthase (TS), a chemotherapeutic target. Besides retrieving the substrate and several known inhibitors, DOCK proposed putative inhibitors previously unknown to bind to the enzyme. Three of these compounds inhibited Lactobacillus casei TS at submillimolar concentrations. One of these inhibitors, sulisobenzone, crystallized with TS in two configurations that differed from the DOCK-favored geometry: a counterion was bound in the substrate site, which resulted in a 6 to 9 angstrom displacement of the inhibitor. The structure of the complexes suggested another binding region in the active site that could be exploited. This region was probed with molecules sterically similar to sulisobenzone, which led to the identification of a family of phenolphthalein analogs that inhibit TS in the 1 to 30 micromolar range. These inhibitors do not resemble the substrates of the enzyme. A crystal structure of phenolphthalein with TS shows that it binds in the target site in a configuration that resembles the one suggested by DOCK.

https://science.sciencemag.org/content/sci/259/5100/1445.full.pdf

Structure-based discovery of inhibitors of thymidylate synthase

Solvation plays an important role in ligand-protein association and has a strong impact on comparisons of binding energies for dissimilar molecules. When databases of such molecules are screened for complementarity to receptors of known structure, as often occurs in structure-based inhibitor discovery, failure to consider ligand solvation often leads to putative ligands that are too highly charged or too large. To correct for the different charge states and sizes of the ligands, we calculated electrostatic and non-polar solvation free energies for molecules in a widely used molecular database, the Available Chemicals Directory (ACD). A modified Born equation treatment was used to calculate the electrostatic component of ligand solvation. The non-polar component of ligand solvation was calculated based on the surface area of the ligand and parameters derived from the hydration energies of apolar ligands. These solvation energies were subtracted from the ligand-receptor interaction energies. We tested the usefulness of these corrections by screening the ACD for molecules that complemented three proteins of known structure, using a molecular docking program. Correcting for ligand solvation improved the rankings of known ligands and discriminated against molecules with inappropriate charge states and sizes.

https://users.cs.duke.edu/~brd/Teaching/Bio/asmb/current/Papers/Lit4Docking/solvationDocking.pdf

Ligand solvation in molecular docking.

Molecular docking algorithms suggest possible structures for molecular complexes. They are used to model biological function and to discover potential ligands. A present challenge for docking algorithms is the treatment of molecular flexibility. Here, the rigid body program, DOCK, is modified to allow it to rapidly fit multiple conformations of ligands. Conformations of a given molecule are pre-calculated in the same frame of reference, so that each conformer shares a common rigid fragment with all other conformations. The ligand conformers are then docked together, as an ensemble, into a receptor binding site. This takes advantage of the redundancy present in differing conformers of the same molecule. The algorithm was tested using three organic ligand protein systems and two protein-protein systems. Both the bound and unbound conformations of the receptors were used. The ligand ensemble method found conformations that resembled those determined in X-ray crystal structures (RMS values typically less than 1.5 A). To test the method's usefulness for inhibitor discovery, multi-compound and multi-conformer databases were screened for compounds known to bind to dihydrofolate reductase and compounds known to bind to thymidylate synthase. In both cases, known inhibitors and substrates were identified in conformations resembling those observed experimentally. The ligand ensemble method was 100-fold faster than docking a single conformation at a time and was able to screen a database of over 34 million conformations from 117,000 molecules in one to four CPU days on a workstation.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/pro.5560070411

Flexible ligand docking using conformational ensembles.

Over the last few decades, computer-aided drug design has emerged as a powerful technique playing a crucial role in the development of new drug molecules. Structure-based drug design and ligand-based drug design are two methods commonly used in computer-aided drug design. In this article, we discuss the theory behind both methods, as well as their successful applications and limitations. To accomplish this, we reviewed structure based and ligand based virtual screening processes. Molecular dynamics simulation, which has become one of the most influential tool for prediction of the conformation of small molecules and changes in their conformation within the biological target, has also been taken into account. Finally, we discuss the principles and concepts of molecular docking, pharmacophores and other methods used in computer-aided drug design.

Computer Aided Drug Design: Success and Limitations.

Searching techniques for databases of two- and three-dimensional chemical structures.

In the past decade, the scientific community has realized the value of three-dimensional (3D) structural information and '3D searching' has started to become an important new methodology for computer-aided drug design. During this time, molecular modeling information generated from various sources has proliferated due to the growing availability of software and hardware and the increasing use of crystallographic and spectroscopic techniques. This information needs to be organized to allow for its effective storage and retrieval. This paper presents an approach to address this problem with a recently introduced program, MACCS-3D. In particular, this approach utilizes MACCS-3D's capability of handling data specific for atoms and atom pairs. With this software, various biological, computational, and spectroscopic data can be merged, allowing scientists from different disciplines to access and use this information more efficiently.

Osman F. Guner

Papers

An integrated approach to three-dimensional information management with MACCS-3D