Structural Aspects of Photopharmacology: Insight into the Binding of Photoswitchable and Photocaged Inhibitors to the Glutamate Transporter Homologue

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(3), P. 1513 - 1520

Published: Jan. 15, 2021

Photopharmacology addresses the challenge of drug selectivity and side effects through creation photoresponsive molecules activated with light high spatiotemporal precision. This is achieved incorporation molecular photoswitches photocages into pharmacophore. However, structural basis for light-induced modulation inhibitory potency in general still missing, which poses a major design this emerging field research. Here we solved crystal structures glutamate transporter homologue GltTk complex transport inhibitors—azobenzene derivative TBOA (both trans cis configuration) photocaged compound ONB-hydroxyaspartate. The essential role transporters functioning central nervous system renders them potential therapeutic targets treatment neurodegenerative diseases. obtained provide clear insight origins photocontrol photopharmacology lay foundation application photocontrolled ligands to study dynamics by using time-resolved X-ray crystallography.

Language: Английский

---

A guide to designing photocontrol in proteins: methods, strategies and applications

Biological Chemistry, Journal Year: 2022, Volume and Issue: 403(5-6), P. 573 - 613

Published: March 31, 2022

Light is essential for various biochemical processes in all domains of life. In its presence certain proteins inside a cell are excited, which either stimulates or inhibits subsequent cellular processes. The artificial photocontrol specifically growing interest the investigation scientific questions on organismal, and molecular level as well development medicinal drugs biocatalytic tools. For targeted design proteins, three major methods have been developed over last decades, employ chemical engineering small-molecule photosensitive effectors (photopharmacology), incorporation photoactive non-canonical amino acids by genetic code expansion (photoxenoprotein engineering), fusion with photoreactive biological modules (hybrid protein optogenetics). This review compares different their strategies current applications light-regulation provides background information useful implementation each technique.

Language: Английский

---

Photoswitchable Diazocine-Based Estrogen Receptor Agonists: Stabilization of the Active Form inside the Receptor

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(33), P. 15059 - 15071

Published: Aug. 11, 2022

Photopharmacology is an emerging approach in drug design and pharmacological therapy. Light used to switch a pharmacophore between biologically inactive active isomer with high spatiotemporal resolution at the site of illness, thus potentially avoiding side effects neighboring healthy tissue. The most frequently strategy photoswitchable replace suitable functional group known bioactive molecule azobenzene. Our different that photoswitch moiety closer drug's scaffold. Docking studies reveal very structural similarity natural 17β-estradiol E isomers dihydroxy diazocines, but not their Z isomers, respectively. Seven diazocines were synthesized subjected biological estrogen reporter gene assay. Four derivatives exhibit distinct estrogenic activity after irradiation violet light, which can be shut off green light. Most remarkably, photogenerated, form one compounds isomerizes back half-life merely several milliseconds water, nevertheless for more than 3 h presence receptor. results suggest significant local impact ligand-receptor complex toward back-isomerization. Thus, drugs are when bound lose immediately leaving receptor could great value because they strongly increase target specificity. Moreover, released into environment form. latter argument particularly important act as endocrine disruptors.

Language: Английский

---

Rational Design in Photopharmacology with Molecular Photoswitches

Angewandte Chemie, Journal Year: 2023, Volume and Issue: 135(30)

Published: April 7, 2023

Abstract Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into structure biologically active small molecules to allow optical control their potency. Going beyond trial and error, photopharmacology has progressively applied rational design methodologies devise light‐controlled bioactive ligands. this review, we categorize photopharmacological efforts from standpoint medicinal chemistry strategies, focusing on diffusible photochromic ligands modified that operate through E‐Z bond isomerization. vast majority cases, photoswitchable designed as analogs existing compounds, a variety approaches. By analyzing in detail comprehensive list instructive examples, describe state art discuss future opportunities photopharmacology.

Language: Английский

---

Optical Control of Adenosine A_2A Receptor Using Istradefylline Photosensitivity

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(3), P. 645 - 655

Published: Jan. 26, 2024

In recent years, there has been growing interest in the potential therapeutic use of inhibitors adenosine A

Language: Английский

---