Class II-selective histone deacetylase inhibitors. Part 2: alignment-independent GRIND 3-D QSAR, homology and docking studies.
(Aryloxopropenyl)pyrrolyl hydroxamates were recently reported by us as first examples of class II-selective HDAC inhibitors and can be useful tools to probe the biology of such enzymes. Molecular modelling and 3-D QSAR studies have been performed on a series of 25 (aryloxopropenyl)pyrrolyl hydroxamates to gain insights about their activity and selectivity against both maize HD1-B and HD1-A, two enzymes homologous of mammalian class I and class II HDACs, respectively. The studies have been accomplished by calculating alignment-independent descriptors (GRIND descriptors) using the ALMOND software. Highly descriptive and predictive 3-D QSAR models were obtained using either class I or class II inhibitory activity displaying r(2)/q(2) values of 0.96/0.81 and 0.98/0.85 for HD1-B and HD1-A, respectively. A deeper inspection revealed that in general a bent molecular shape structure is a prerequisite for HD1-A-selective inhibitory activity, while straight shape molecular skeleton leads to selective HD1-B compounds. The same conclusions could be achieved by molecular docking studies of the most selective inhibitors.
Ragno
Rino
R
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy. rino.ragno@uniroma1.it
Simeoni
Silvia
S
Rotili
Dante
D
Caroli
Antonella
A
Botta
Giorgia
G
Brosch
Gerald
G
Massa
Silvio
S
Mai
Antonello
A
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D017386:Sequence Homology, Amino Acid; D012984:Software; D013379:Substrate Specificity; D003313:Zea mays / Q000201:enzymology
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D006655:Histone Deacetylases