Enabling Large-Scale Design, Synthesis and Validation of Small Molecule Protein-Protein Antagonists

Abstract

Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure.

Multicomponent Reactions, Union of MCRs and Beyond

“…The free web-, anchor-, and pharmacophore-based server AnchorQuery (http://anchorquery.ccbb.pitt.edu/), for example, allows for the screening of a very large virtual MCR library with over a billion members. [32] AnchorQuery builds on the role that deeply buried amino acid side chains or other anchors play in proteinprotein interactions. Based on the efficient and convergent nature of MCR chemistry, proposed virtual screening hits can be instantaneously synthesized and tested.…”

Pharmacophore Modeling: Methods and Applications

“…More specific interaction features, such as metal interactions [21], may also be specified. Highly specific features that map directly to specific functional groups (e.g., mimics of protein side chains [22]) violate the strict definition of a pharmacophore, but may still be useful for virtual screening purposes.…”

“…More recently, index-based methods of searching, which scale with the breadth and complexity of the query, not the database size, were developed for searching and aligning libraries of rigid conformers. AnchorQuery [22] is limited to chemical spaces containing a predefined 'anchor' fragment that is used to define the coordinate system of the molecule. Pharmacophore features of rigid conformations are then stored in a spatial index at these anchor-oriented coordinates.…”

Efficient Assembly of Iminodicarboxamides by a “Truly” Four‐Component Reaction

“…[19] Our herein reported one-pot synthesis towards this scaffold comprises a major advancement and is superior to reported stepwise sequential or MCR approaches, in terms of yield, time, effort, stereochemistry and breath of useful starting materials. [20] The scope of the extended Ugi 4-CR is good in all investigated starting materials and a very large number of products are theoretically accessible.…”

“…This is significant since recent trends in drug discovery using MCR chemistry more and more leverage the usage of virtual screening tools. [19,21] Towards this end we introduced a freely accessible virtual compound library of ~5 million compounds based on this backbone in the recently published ANCHOR.QUERY software for the discovery of protein-protein interaction antagonists. [19] In conclusion we described a novel and rare case of a 4CR where all four starting material classes can be widely combined which each other.…”