Taechalertpaisarn, Jaru (2018-05). Design, Optimization and Syntheses of Small Molecules to Disrupt Protein-Protein Interactions. Doctoral Dissertation. Thesis uri icon

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 C?-Css coordinates of virtual small molecules to the side-chain vectors of proteins at PPI interfaces. Similar C?-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 NefoMHC-IoAP1 and NEDD8oNAE 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 PCSK9oLDLR interaction that causes hypercholesterolemia disease. Although the firstgeneration hydantoin-piperazine derivatives did not show good PCSK9oLDLR 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 PCSK9oLDLR 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.
  • 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 C?-Css
    coordinates of virtual small molecules to the side-chain vectors of proteins at PPI
    interfaces. Similar C?-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 NefoMHC-IoAP1 and NEDD8oNAE
    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
    PCSK9oLDLR interaction that causes hypercholesterolemia disease. Although the firstgeneration
    hydantoin-piperazine derivatives did not show good PCSK9oLDLR 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 PCSK9oLDLR 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.

publication date

  • May 2018