Generation of New Synthetic Scaffolds Using Framework Libraries Selected and Refined via Medicinal Chemist Synthetic Expertise

Abstract

With the expansion in the application of library methods in medicinal chemistry and chemical biology there is a growing need for improved technology for the design of novel templates that are well suited for the synthesis of libraries targeted toward specific subsets of protein families. In this report, we delineate an improved stepwise general method that is well suited for this purpose. This process uses virtual framework libraries to identify frameworks that rigidly match specific aspects of a ligand's bioactive conformation. The resulting frameworks can then be ranked and sequentially modified by a combination of computational scripts and human derived expertise, in order to develop rational proposals for new combinatorial templates or new sets of potential ligands.

Design and synthesis of a novel tyrosine kinase inhibitor template

“…We report the details on the specific application of our recently published ‘framework’ design1 of a new kinase inhibitor template and the synthesis of the subject of this design, a novel tetracyclic pyridone tyrosine kinase inhibitor template, which was accomplished in 8 steps 26. This synthesis involves a one pot di- ortho -substituted aldehyde condensation, followed by the cyanide-catalyzed cyclization, which gave the key indole intermediate in >70% yield.…”

“…However, in some cases, it is possible to design ‘hits’ if sufficient information is available. We have recently published a detailed report on a novel and general method for de novo protein ligand design that uses pharmacophore-based geometry queries, or other similar information, to search virtual hydrocarbon databases for rigid frameworks that match the geometry of the query 1. These new frameworks can then be used as starting points in the design of new structures that contain the constrained pharmacophore interaction features 1.…”

“…We have recently published a detailed report on a novel and general method for de novo protein ligand design that uses pharmacophore-based geometry queries, or other similar information, to search virtual hydrocarbon databases for rigid frameworks that match the geometry of the query 1. These new frameworks can then be used as starting points in the design of new structures that contain the constrained pharmacophore interaction features 1. One of the general applications of this design method makes use of a pharmacophore query derived from the bound conformation of an inhibitor, as observed in a protein-inhibitor crystal structure 2.…”

“…Using the general published approach,1 we searched a virtual framework library (VFL) using the pharmacophore shown in Figure 1, which was derived from a co-crystal structure of a ligand bound to the non-activated IGF1R kinase domain 2. We utilized a pharmacophore with all of the interaction features converted to hydrophobic for the initial search of the VFL, as previously described 1–3.…”

“…We utilized a pharmacophore with all of the interaction features converted to hydrophobic for the initial search of the VFL, as previously described 1–3. This search yielded a large number of polycyclic framework hits that were then subjected to selection based on synthetic and medicinal chemistry expertise.…”