Synthesis, in vitro biological investigation, and molecular dynamics simulations of thiazolopyrimidine based compounds as corticotrophin releasing factor receptor-1 antagonists
Elgiushy, Hossam R; Abou-Taleb, Nageh A; Holz, George G; Chepurny, Oleg G; Pirmettis, Ioannis; Kakabakos, Sotirios; Karageorgos, Vlasios; Liapakis, George; Albohy, Amgad; Abouzid, Khaled; Hammad, Sherif F;
Abstract
Corticotrophin releasing factor receptor-1 (CRFR1) is a potential target for treatment of depression and anxiety through modifying stress response. A series of new thiazolo[4,5-d]pyrimidine derivatives were designed, prepared and biologically evaluated as potential CRFR1 antagonists. Four compounds produced more than fifty percent inhibition in the [125I]-Tyr0-sauvagine specific binding assay. Assessment of binding affinities revealed that compound (3-(2,4-dimethoxyphenyl)-7-(dipropylamino)-5-methylthiazolo[4,5-d]pyrimidin-2(3H)-one) 8c was the best candidate with highest binding affinity (Ki = 32.1 nM). Further evaluation showed the ability of compound 8c to inhibit CRF induced cAMP accumulation in a dose response manner. Docking and molecular dynamics simulations were used to investigate potential binding modes of synthesized compounds as well as the stability of 8c-CRFR1 complex. These studies suggest similar allosteric binding of 8c compared to that of the co-crystalized ligand CP-376395 in 4K5Y pdb file.
Other data
Title | Synthesis, in vitro biological investigation, and molecular dynamics simulations of thiazolopyrimidine based compounds as corticotrophin releasing factor receptor-1 antagonists | Authors | Elgiushy, Hossam R; Abou-Taleb, Nageh A; Holz, George G; Chepurny, Oleg G; Pirmettis, Ioannis; Kakabakos, Sotirios; Karageorgos, Vlasios; Liapakis, George; Albohy, Amgad; Abouzid, Khaled ; Hammad, Sherif F | Keywords | CRFR1 antagonists;Thiazolo[4,5-d]pyrimidine;Scaffold hopping;Molecular dynamics simulation | Issue Date | Sep-2021 | Publisher | ACADEMIC PRESS INC ELSEVIER SCIENCE | Journal | Bioorganic Chemistry | Volume | 114 | ISSN | 0045-2068 | DOI | 10.1016/j.bioorg.2021.105079 | PubMed ID | 34174633 | Scopus ID | 2-s2.0-85108604766 | Web of science ID | WOS:000691056300003 |
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