Mapping the Azolog Space Enables the Optical Control of New Biological Targets

Abstract

Photopharmacology relies on molecules that change their biological activity upon irradiation. Many of these are derived from known drugs by replacing their core with an isosteric azobenzene photoswitch (azologization). The question is how many of the known bioactive ligands could be addressed in such a way. Here, we systematically assess the space of molecules amenable to azologization from databases of bioactive molecules (DrugBank, PDB, CHEMBL) and the Cambridge Structural Database. Shape similarity scoring functions (3DAPfp) and analyses of dihedral angles are employed to quantify the structural homology between a bioactive molecule and the cis or trans isomer of its corresponding azolog (“azoster”) and assess which isomer is likely to be active. Our analysis suggests that a very large number of bioactive ligands (>40 000) is amenable to azologization and that many new biological targets could be addressed with photopharmacology. N -Aryl benzamides, 1,2-diarylethanes, and benzyl phenyl ethers are particularly suited for this approach, while benzylanilines and sulfonamides appear to be less well-matched. On the basis of our analysis, the majority of azosters are expected to be active in their trans form. The broad applicability of our approach is demonstrated with photoswitches that target a nuclear hormone receptor (RAR) and a lipid processing enzyme (LTA 4 hydrolase).

Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers

“…Depending on their electronic nature and substitution pattern, they can thermally isomerize back to their trans-form in at unable fashion, with thermal half-lives ranging from nanoseconds to days under physiological conditions.A lthough several azobenzene photoswitches have been reported to be biologically active in their thermodynamically less stable cis-form, [10,[26][27][28] the majority are more active in the dark, that is,a st heir thermodynamically more stable trans-isomers.T his is,i np art, because their parent compounds tend to bind in elongated or stretched conformations,a sd emonstrated by ar ecent computational analysis of drug-like molecules that are suitable to azologization. [29] Cyclic azobenzene photoswitches,a lso known as diazocines,w herein the diazene unit is embedded in an eightmembered ring, have been known for many years but were only recently photophysically and conformationally characterized by Temps and Herges. [30][31][32][33][34] In contrast to standard azobenzenes,t heir bent cis-isomer is thermodynamically more stable and predominates in the dark, while exposure to light in the violet or deep blue range of the visible light spectrum promotes the formation of the thermodynamically less stable,e longated trans-isomer.W ep ostulated that the stable cis-isomer of the diazocine could effectively mimic the cis-isomer of as tandard azobenzene,w hereas the elongated trans-diazocine would sterically resemble the trans-isomer of as tandard azobenzene.S imilar to azobenzenes,d iazocines undergo al arge change in dipole moment upon isomerization.…”

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

“…amide, ether, alkane or alkyne). 8 In the case of azobenzene the bridge is a diazene group (also called azo group) and depending on the wavelength of illumination, a linear trans isomer or a bent cis isomer can be obtained. 9 In this way, if a biaryl moiety is replaced by an azobenzene (i.e.…”

“…azologization approach), there is relatively good chance that one of the resulting photoisomers will have a similar spatial disposition to the original biaryl unit and, therefore, a similar biological activity that might change upon isomerization of the 2 azobenzene. 8 The second reason for the success of azobenzene in the photopharmacology field is the robust photoisomerization. It provides typically high yields of photoisomerization with relatively low intensity of light and minimal photobleaching even over hundreds of cycles.…”

Optical control of the nuclear bile acid receptor FXR with a photohormone

“…Recently, we demonstrated that the azobenzene-containing retinoic acid receptor a (RARa) agonist Azo80 11 allows for optical control of RARa. 12 We envisioned that photoswitchable NHR modulators, termed 'photohormones', could facilitate progress in the study of NHRs. Herein, we describe the development of a photoswitchable FXR agonist, termed AzoGW.…”

“…These results suggest reduced potency of the cis-isomer in keeping with the predictions of our chemoinformatic azologization study. 12 To explore if AzoGW allows for light-dependent activation of FXR, we carried out a luminescent reporter gene assay for human FXR, where the ligand-binding dependent activation of FXR is coupled to the expression of the reporter gene rey luciferase. We used varying concentrations of GW4064 and AzoGW (Fig.…”