TY - JOUR
T1 - Combined ligand and fragment-based drug design of selective histone deacetylase – 6 inhibitors
AU - Ruzic, Dusan
AU - Petkovic, Milos
AU - Agbaba, Danica
AU - Ganesan, A.
AU - Nikolic, Katarina
PY - 2019/5
Y1 - 2019/5
N2 - Histone deacetylase 6 (HDAC6) is unique hydrolase within HDAC family, having pleiotropic deacetylase activity against α-tubulin, cortactin and dynein. Comprehensively, HDAC6 controls cell motility, apoptosis and protein folding, whereas alterations in its structure and function are related to the pathogenesis of cancer, neurodegeneration and inflammation. To define structural motifs which guide HDAC6 selectivity, we developed and compared three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) models for HDAC1 and HDAC6 inhibitors. The reduction of the bias in conformer generation was supported by virtual docking study by using crystal structures of human HDAC1 and HDAC6 isoforms. Following these findings, the combined ligand-based and fragment-based drug design methodologies were used in the design of selective HDAC6 inhibitors. Group of the most promising novel ligands was selected based on the predicted HDAC6 selectivity, pharmacokinetic profile, synthetic tractability, and in silico cytotoxicity against the wide range of human cancer cell lines.
AB - Histone deacetylase 6 (HDAC6) is unique hydrolase within HDAC family, having pleiotropic deacetylase activity against α-tubulin, cortactin and dynein. Comprehensively, HDAC6 controls cell motility, apoptosis and protein folding, whereas alterations in its structure and function are related to the pathogenesis of cancer, neurodegeneration and inflammation. To define structural motifs which guide HDAC6 selectivity, we developed and compared three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) models for HDAC1 and HDAC6 inhibitors. The reduction of the bias in conformer generation was supported by virtual docking study by using crystal structures of human HDAC1 and HDAC6 isoforms. Following these findings, the combined ligand-based and fragment-based drug design methodologies were used in the design of selective HDAC6 inhibitors. Group of the most promising novel ligands was selected based on the predicted HDAC6 selectivity, pharmacokinetic profile, synthetic tractability, and in silico cytotoxicity against the wide range of human cancer cell lines.
KW - 3D-QSAR
KW - Epidrugs
KW - HDAC6
KW - Rational drug design
UR - http://www.scopus.com/inward/record.url?scp=85059916833&partnerID=8YFLogxK
U2 - 10.1002/minf.201800083
DO - 10.1002/minf.201800083
M3 - Article
AN - SCOPUS:85059916833
VL - 38
JO - Molecular Informatics
JF - Molecular Informatics
SN - 1868-1743
IS - 5
M1 - 1800083
ER -