“The majority of scaffold-hopping methods in the literature use ligand-based descriptors in a search for core replacements,” she said. “However, the search can be focused on a more relevant chemical space by utilizing structural information from the receptor.”
Shelley described a structure-based core-hopping method in CombiGlide, which can systematically evaluate and rank a large collection of candidate core structures in the presence of the receptor.
“We have created a method for evaluating a collection of core candidates starting from a lead compound (template) that is well positioned in a receptor. Candidate structures are evaluated based on geometric alignments with the template as well as the interactions with the receptor.”
Each scaffold aligned with the template must fit also into the receptor, Shelley explained. After side chains are added from the template and the position and conformation are refined, researchers can then rank core-hopped structures based on docking scores. The result is a flexible platform on which multiple applications using core hopping are possible.
“You can find replacement rings or linkers. You can also expand the core region and search with larger candidate structures, e.g., fragments generated using RECAP rules. Another area we have been exploring recently is to use our core-hopping method in conjunction with fragment-based drug discovery—all these are possible on this platform,” said Shelley.
Scaffold hopping, or lead hopping, can be defined as the identification of isofunctional molecular structures with significantly different molecular backbones. Virtual screening and de novo design are two computational techniques that have been applied successfully in the past to generate new hits and lead candidates in early drug discovery.
Ingo Mügge, senior associate director, CADD, Boehringer Ingelheim Pharmaceuticals, discussed how these well-known computational approaches can guide researchers toward new scaffolds with more favorable properties beginning from known ligands.
“A central premise of medicinal chemistry is that structurally similar molecules have similar biologic chemistry,” said Mügge. “A counterpremise is that structurally different molecules can produce similar biologic activities, thus producing the premise for scaffold hopping.”
Looking at the statistics, Mügge noted, the more pharmacophore restraints that are set, the greater the scaffolds reduction will be. “Exhaustive ring replacement works well if many pharmacophoric constraints are known. If no constraints are set for even small ring systems, the number of solutions may be overwhelming.”
Mügge described de novo design with BIBuilder. “The goals are to design high-quality molecular structures using tractable synthesis routes. Results should be drug-like and devoid of unwanted structures and/or circumvent intellectual property constraints. In addition, results will represent prospective new lead series that will require further optimization.”
Two case studies in which BIBuilder was utilized were reviewed by Mügge. His group prepared a set of ligands representing unique chemotypes for seven diverse drug targets, prepared negative controls from MDDR, calculated various descriptors (2-D topological and 3-D), performed a structure-based virtual screen, and then ranked the compounds along several parameters and compared the results.
In the first case, there was no topological bias, as actives were as (dis)similar to each other as they were to negative controls. However, in the second case, actives were more similar to each other than they were to negative controls, creating a topological bias.
“Based on whether you want to conservatively replace the core or whether you want to create a completely new molecule, you can adjust this tool accordingly,” said Mügge. “The more you know about the nature of the core, the more specific the parameters you can place.
“Once you produce a number of compound ideas, that is the time to go to the chemist and pick their brains and make final synthesis decisions” said Mügge. “This is a conservative—but effective—approach.”