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3D-QSAR and molecular docking studies on fused pyrazoles as p38? mitogen-activated protein kinase inhibitors.

ABSTRACT: The p38? mitogen-activated protein kinase (MAPK) has become an attractive target for the treatment of many diseases such as rheumatoid arthritis, inflammatory bowel disease and Crohn's disease. In this paper, 3D-QSAR and molecular docking studies were performed on 59 p38? MAPK inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to determine the structural requirements for potency in inhibiting p38? MAPK. The resulting model of CoMFA and CoMSIA exhibited good r(2) (cv) values of 0.725 and 0.609, and r(2) values of 0.961 and 0.905, respectively. Molecular docking was used to explore the binding mode between the inhibitors and p38? MAPK. We have accordingly designed a series of novel p38? MAPK inhibitors by utilizing the structure-activity relationship (SAR) results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provided a useful guide to design new compounds for p38? MAPK inhibitors.

SUBMITTER: Lan P

PROVIDER: S-EPMC2956100 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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3D-QSAR and molecular docking studies on fused pyrazoles as p38α mitogen-activated protein kinase inhibitors.

Lan Ping P Huang Zhi-Jian ZJ Sun Jun-Rong JR Chen Wei-Min WM

International journal of molecular sciences 20100917 9

The p38α mitogen-activated protein kinase (MAPK) has become an attractive target for the treatment of many diseases such as rheumatoid arthritis, inflammatory bowel disease and Crohn's disease. In this paper, 3D-QSAR and molecular docking studies were performed on 59 p38α MAPK inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to determine the structural requirements for potency in inhibiting p38α MAPK. The resulti ...[more]

PMID: 20957100

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Project description:Mitogen-activated protein kinases (MAPK) are important regulatory units in cells and they take part in the regulation of many cellular functions such as cell division, differentiation or apoptosis. All MAPKs have a shallow docking groove that interacts with linear binding motifs of their substrate proteins and their regulatory proteins such as kinases, phosphatases, scaffolds. Inhibition of these protein-protein interactions may reduce or abolish the activity of the targeted kinase. Based on the wide range of their biological activity, this kind of inhibition can be useful in the treatment of many disorders like tumors, inflammation or undesired cell apoptosis. In this study a linear binding motif from the RHDF1 protein-a 15 amino acids long peptide-was selected for optimization to increase its cellular uptake but retaining its low micromolar binding affinity. First, we synthesized an octaarginine conjugate that showed efficient cellular uptake. Next, we set out to reduce the size of this construct. We were able to decrease the length of the original peptide, and to increase its cellular uptake with specific chemical modifications. These new constructs bound better to ERK2 and p38 kinases than the original peptide and they showed markedly increased cellular uptake. The new octaarginine conjugate and one of the minimized bicyclic derivatives could inhibit the phosphorylation of intracellular ERK or p38. However, the modulation of MAPK phosphorylation levels by these cell-penetrating peptides were complex, despite that in biochemical assays they all inhibited MAPK-substrate binding as well as phosphorylation. The optimized peptides depending on the applied concentration caused an expected decrease, but also some unexpected increase in MAPK phosphorylation patterns in the cell. This possibly reflects the complexity of MAPK docking groove mediated protein-protein interactions including bone fide MAPK clients such activator kinases, deactivating phosphatases or regulatory scaffolds. Thus, our findings with optimized cell-penetrating "inhibitory" peptides highlight the opportunities but also the pitfalls of docking peptide based MAPK activity regulation and call for a better quantitative understanding of MAPK mediated protein-protein interactions in cells.

Dataset Information

3D-QSAR and molecular docking studies on fused pyrazoles as p38? mitogen-activated protein kinase inhibitors.

Publications

3D-QSAR and molecular docking studies on fused pyrazoles as p38α mitogen-activated protein kinase inhibitors.

Similar Datasets

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