Computational insights into the interaction of small molecule inhibitors with HRI kinase domain.
J Biomol Struct Dyn
; 37(7): 1715-1723, 2019 Apr.
Article
em En
| MEDLINE
| ID: mdl-29663856
ABSTRACT
The Heme-Regulated Inhibitor (HRI) kinase regulates globin synthesis in a heme-dependent manner in reticulocytes and erythroid cells in bone marrow. Inhibitors of HRI have been proposed to lead to an increased amount of haemoglobin, benefitting anaemia patients. A series of indeno[1,2-c]pyrazoles were discovered to be the first known in vitro inhibitors of HRI. However, the structural mechanism of inhibition is yet to be understood. The aim of this study was to unravel the binding mechanism of these inhibitors using molecular dynamic simulations and docking. The docking scores were observed to correlate well with experimentally determined pIC50 values. The inhibitors were observed to bind in the ATP-binding site forming hydrogen bonds with the hinge region and van der Waals interactions with non-polar residues in the binding site. Further, quantitative structure-activity relationship (QSAR) studies were performed to correlate the structural features of the inhibitors with their biological activity. The developed QSAR models were found to be statistically significant in terms of internal and external predictabilities. The presence of chlorine atoms and the hydroxymethyl groups were found to correlate with higher activity. The identified binding modes and the descriptors can support future rational identification of more potent and selective small molecule inhibitors for this kinase which are of therapeutic importance in the context of various human pathological disorders.
Palavras-chave
2-c]pyrazoles; ATP Adenosine triphosphate; BLAST Basic Local Alignment Search Tool; EIF2AK1; EIF2AK1 Eukaryotic Initiation factor alpha kinase I; GCN2 General Control Non-derepressible 2 Kinase; HRI; HRI Heme Regulated Inhibitor Kinase; MLR Multiple Linear Regression; PDB Protein Databank; PERK PKR-like Endoplasmic Reticulum Kinase; PKR RNA-dependent Protein Kinase; QSAR Quantitative StructureActivity Relationship; docking; indeno[1; inhibitors; kNN-MFA k-Nearest Neighbour Molecular Field Analysis
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sítios de Ligação
/
EIF-2 Quinase
/
Inibidores de Proteínas Quinases
/
Domínios e Motivos de Interação entre Proteínas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article