Discovery of novel integrase-LEDGF/p75 allosteric inhibitors based on a benzene scaffold

Autor:	Tamura Yoshinori, Kenji Tomita, Tomokazu Yoshinaga, Shuhei Arita, Shuichi Sugiyama, Takahiro Seki, Tsutomu Iwaki, Eriko Matsuoka, Takashi Kawasuji
Rok vydání:	2020
Předmět:	Scaffold Stereochemistry Cell Survival Clinical Biochemistry Allosteric regulation Human immunodeficiency virus (HIV) Drug Evaluation Preclinical Pharmaceutical Science medicine.disease_cause Crystallography X-Ray 01 natural sciences Biochemistry Antiviral Agents Cell Line chemistry.chemical_compound Structure-Activity Relationship Allosteric Regulation Drug Discovery Pyridine medicine Benzene Derivatives Animals Humans Benzene Molecular Biology chemistry.chemical_classification Sulfonamides Binding Sites biology 010405 organic chemistry Organic Chemistry 0104 chemical sciences Sulfonamide Integrase Rats Molecular Docking Simulation 010404 medicinal & biomolecular chemistry chemistry biology.protein Microsomes Liver Molecular Medicine Intercellular Signaling Peptides and Proteins Linker Half-Life
Zdroj:	Bioorganicmedicinal chemistry. 28(17)
ISSN:	1464-3391
Popis:	We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent antiviral activity (EC50 (NL432) = 3.9 nM) than BI-224436 (EC50 (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3d282840ea7eda4da7b24fbde8df0b8a https://pubmed.ncbi.nlm.nih.gov/32773094 Zobrazit plný text záznamu Full Text from ScienceDirect