Design, Optimization and Syntheses of Small Molecules to Disrupt Protein-Protein Interactions

Abstract

Protein-protein interactions (PPIs) are one of the basic mechanisms in cellular biology, but also involve in diseases if they are dysregulation. Disrupting aberrant PPI activities is useful in medicinal chemistry. One approach to inhibit PPIs is to design small molecule peptidomimetics bearing side-chain orientations similar to protein ligands, in which those mimics might displace or interfere the native PPIs. Previous research in our group developed Exploring Key Orientations (EKO) program that matches Cɑ-Cß coordinates of virtual small molecules to the side-chain vectors of proteins at PPI interfaces. Similar Cɑ-Cß orientations between mimics and protein ligands indicate that small molecules might be suitable to displace protein ligands, i.e. those compounds might interfere PPIs. We used EKO to deduce small molecules that might disrupt medicinally-relevant PPIs. Herein, EKO implicated our designed mimics, hydantoin-oxazoline, triazole-oxazole and triazole-oxazoline derivatives, might disrupt Nef•MHC-I•AP1 and NEDD8•NAE interactions, in which they are relevant to HIV-1 and cancer diseases respectively. After learning from these projects, we designed hydantoin-piperazine analogues to disrupt PCSK9•LDLR interaction that causes hypercholesterolemia disease. Although the firstgeneration hydantoin-piperazine derivatives did not show good PCSK9•LDLR inhibition, we modified chemotype structures by cooperating with a docking program, Glide, to improve inhibitory potencies. As a result, we successfully obtained lead compounds that significantly disrupt PCSK9•LDLR interaction with the measurable binding affinities. Besides these protein targets, we synthesized another minimalist mimic, oxazoline piperidine-2,4-dione, that has conformational biases toward helical and sheet-turn-sheet motifs. This structure potentially has favorable cellular- and oral-permeability calculated by QikProp. We are also interested in how to design molecules suitable for PPI inhibition. A concept of secondary structure mimicry is widely applied to design molecules that resemble a secondary structure at an PPI interface, hence possibly disrupt protein-protein interaction. However, there is no direct study to prove a correlation between secondary structure mimicry and interface mimicry. To respond this issue, we used EKO to match several new chemotypes on the ideal secondary structures and PPIs database, and then compared the frequencies of secondary structures that chemotypes matched at PPI interfaces to the ideal secondary structure biases of each chemotype. We found that, in general, good secondary structure mimics tend to match frequently at PPI interfaces; however, they mostly match on non-ideal secondary structure motifs.