SAR and QSAR study on 2-aminothiazole derivatives, modulators of transcriptional repression in Huntington's disease.
REST/NRSF is a multifunctional transcription factor that represses or silences many neuron-specific genes in both neural and non-neural cells by recruitment to its cognate RE1/NRSE regulatory sites. An increase in RE1/NRSE genomic binding is found in Huntington's disease (HD), resulting in the repression of REST/NRSF regulated gene transcription, among which BDNF, thus representing one of the possible detrimental effectors in HD. Three 2-aminothiazole derivatives were recently identified as potent modulators of the RE1/NRSE silencing activity through a cell-based gene reporter assay. In this study, the structure-activity relationships (SAR) of a library of commercially available 2-aminoisothiazoles diversely substituted at the amino group or at position 4 has been evaluated. A quantitative structure-activity relationship analysis performed using the Phase strategy yielded highly predictive 3D-QSAR pharmacophore model for in silico drug screening.
Leone
Samantha
S
Istituto di Chimica Organica Alessandro Marchesini, Facoltà di Farmacia, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy.
Mutti
Cesare
C
Kazantsev
Aleksey
A
Sturlese
Mattia
M
Moro
Stefano
S
Cattaneo
Elena
E
Rigamonti
Dorotea
D
Contini
Alessandro
A
D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D015723:Gene Library; D020868:Gene Silencing / Q000187:drug effects; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics*; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D000099229:RE1-Silencing Transcription Factor
D012097:Repressor Proteins; D013844:Thiazoles; D000099229:RE1-Silencing Transcription Factor; C004483:2-aminothiazole