Development of small molecules designed to modulate protein–protein interactions

Abstract

Protein-protein interactions are ubiquitous, essential to almost all known biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein-protein interactions is challenging, owing to the large size of protein-complex interface, the lack of well-defined binding pockets, etc. We describe a general approach based on the "privileged-structure hypothesis" [Che, Ph.D. Thesis, Washington University, 2003] - that any organic templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as protein-complex antagonists--to address the challenges inherent in the discovery of small-molecule inhibitors of protein-protein interactions.

The SCHOOL of nature: I. Transmembrane signaling

“…4B)-biochemical processes that can be influenced and controlled, [209][210][211][212][213] and specific inhibition and/ or modulation of these interactions provides a promising novel approach for rational drug design, as revealed by recent progress in the design of inhibitory antibodies, peptides and small molecules. 129,[213][214][215][216][217][218][219][220] (3) Introducing the CYTO homointeractions between MIRR signaling subunits as one of the key elements of MIRR triggering and signaling, the SCHOOL model imposes functionally important restraints ( Table 2) and suggests molecular mechanisms for the vast majority of unexplained immunological observations accumulated to date. 4,49,97,98,130 (4) Unraveling the molecular mechanisms underlying MIRR triggering and subsequent TM signaling, the model suggests unique and powerful tools to study the immune response and a means to control and/or modulate it.…”

Back to the future: Ribonuclease A

“…Reverse-turn mimetics 103 have been constructed from such diverse structural approaches as cyclically constrained pepti-…”

“…128 Experimental observations and theoretical calculations suggested that helical mimetics based on a triphenyl, tripyridyl, or phenyldipyridyl scaffolds could correctly orient the i, i + 3, i + 4, and i + 7 side chains that formed one side of the surface of an a-helix. 89,92,103 To further investigate the stabilities of helix mimetics, chimeric proteins were designed in silico by ligating four different helix mimetic designs with the bhairpin subdomain of FSD-1 ( Figure 16). A 100-ns MD simulation with GB/SA implicit solvation showed that one of these chimeric proteins was more stable than the native structure and maintained the expected fold during simulations.…”

Protein recognition motifs: Design of peptidomimetics of helix surfaces

“…Accordingly, numerous strategies have been developed to stabilize helical conformations of a peptide. 5 Marshall and Bosshard 6 predicted in 1972 that a,a-dialkyl amino, such as aminoisobutyric acid (Aib) acids, would severely restrict the F and C torsion angles of that residue to those associated with right-or left-handed helices (both a-and 3 10 -helices). Subsequent experimental validation of that prediction is abundant.…”

“…7 Alternatively, the helical structure can be stabilized through the incorporation of covalent or noncovalent linkages between side chains of two residues separated in sequence, but spatially close in a helix, such as residues i and i þ 4 of an a-helix. Examples of chemical linkages shown to enhance helical propensity include salt bridges, hydrophobic interactions, aromatic-charge or aromatic-sulfur interactions, disulfide bonds, lactam bridges, hydrocarbon staplings, diaminoalkanes, acetylenes, and metal ligation between natural and unnatural amino acids (for a recent review, see Che et al 5 and references therein). Helical peptides are stabilized by extensive, but weak intrachain H-bonds; design of covalent mimics of intrachain H-bonds reinforces the helical structure.…”