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Design of novel JAK3 Inhibitors towards Rheumatoid Arthritis using molecular docking analysis.

ABSTRACT: Multiple cytokines play a pivotal role in the pathogenesis of Rheumatoid Arthritis by inducing intracellular signaling and it is known that the members of the Janus kinase (JAK) family are essential for such signal transduction. Janus kinase 3 is a tyrosine kinase that belongs to the Janus family of kinases. Drugs targeting JAK3 in the treatment of Rheumatoid arthritis is relevant. Therefore, it is of interest to design suitable inhibitors for JAK3 dimer using molecular docking with Molegro Virtual Docker. The compound possessing the highest affinity score is subjected to virtual screening to retrieve inhibitors. The compound SCHEMBL19100243 (PubChem CID- 76749591) displays a high affinity with the target protein. The affinity scores of this compound are more than known drugs. ADMET analysis and BOILED Egg plot provide insights into this compound as a potent inhibitor of JAK3.

SUBMITTER: Jain D

PROVIDER: S-EPMC6677909 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Design of novel JAK3 Inhibitors towards Rheumatoid Arthritis using molecular docking analysis.

Jain Divya D Udhwani Trishang T Sharma Shreshtha S Gandhe Aishwarya A Reddy Palugulla Bhaskar PB Nayarisseri Anuraj A Singh Sanjeev Kumar SK

Bioinformation 20190228 2

Multiple cytokines play a pivotal role in the pathogenesis of Rheumatoid Arthritis by inducing intracellular signaling and it is known that the members of the Janus kinase (JAK) family are essential for such signal transduction. Janus kinase 3 is a tyrosine kinase that belongs to the Janus family of kinases. Drugs targeting JAK3 in the treatment of Rheumatoid arthritis is relevant. Therefore, it is of interest to design suitable inhibitors for JAK3 dimer using molecular docking with Molegro Virt ...[more]

PMID: 31435152

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Project description:Treatment of several autoimmune diseases and types of cancer has been an intense area of research over the past two decades. Many signaling pathways that regulate innate and/or adaptive immunity, as well as those that induce overexpression or mutation of protein kinases, have been targeted for drug discovery. One of the serine/threonine kinases, Interleukin-1 Receptor Associated Kinase 4 (IRAK4) regulates signaling through various Toll-like receptors (TLRs) and interleukin-1 receptor (IL1R). It controls diverse cellular processes including inflammation, apoptosis, and cellular differentiation. MyD88 gain-of-function mutations or overexpression of IRAK4 has been implicated in various types of malignancies such as Waldenström macroglobulinemia, B cell lymphoma, colorectal cancer, pancreatic ductal adenocarcinoma, breast cancer, etc. Moreover, over activation of IRAK4 is also associated with several autoimmune diseases. The significant role of IRAK4 makes it an interesting target for the discovery and development of potent small molecule inhibitors. A few potent IRAK4 inhibitors such as PF-06650833, RA9 and BAY1834845 have recently entered phase I/II clinical trial studies. Nevertheless, there is still a need of selective inhibitors for the treatment of cancer and various autoimmune diseases. A great need for the same intrigued us to perform molecular modeling studies on 4,6-diaminonicotinamide derivatives as IRAK4 inhibitors. We performed molecular docking and dynamics simulation of 50 ns for one of the most active compounds of the dataset. We also carried out MM-PBSA binding free energy calculation to identify the active site residues, interactions of which are contributing to the total binding energy. The final 50 ns conformation of the most active compound was selected to perform dataset alignment in a 3D-QSAR study. Generated RF-CoMFA (q2 = 0.751, ONC = 4, r2 = 0.911) model revealed reasonable statistical results. Overall results of molecular dynamics simulation, MM-PBSA binding free energy calculation and RF-CoMFA model revealed important active site residues of IRAK4 and necessary structural properties of ligand to design more potent IRAK4 inhibitors. We designed few IRAK4 inhibitors based on these results, which possessed higher activity (predicted pIC50) than the most active compounds of the dataset selected for this study. Moreover, ADMET properties of these inhibitors revealed promising results and need to be validated using experimental studies.

Project description:Background: This study aimed to investigate the molecular mechanism of Radix Paeoniae Alba (white peony, WP) in treating immune inflammatory diseases of rheumatoid arthritis (RA) and tumor necrosis factor-alpha (TNF-α) inhibitors (TNFis) by using network pharmacology and molecular docking. Methods: In this study, the ingredient of WP and the potential inflammatory targets of RA were obtained from the Traditional Chinese Medicine Systematic Pharmacology Database, GeneCard, and OMIM databases, respectively. The establishment of the RA-WP-potential inflammatory target gene interaction network was accomplished using the STRING database. Network maps of the WP-RA-potential inflammatory target gene network were constructed using Cytoscape software. Gene ontology (GO) and the biological pathway (KEGG) enrichment analyses were used to further explore the RA mechanism and therapeutic effects of WP. Molecular docking technology was used to analyze the optimal effective components from WP for docking with TNF-α. Results: Thirteen active ingredients and 71 target genes were screened from WP, and 49 of the target genes intersected with RA target inflammatory genes and were considered potential therapeutic targets. Network pharmacological analysis showed that the WP active ingredients such as mairin, DPHCD, (+)-catechin, beta-sitosterol, paeoniflorin, sitosterol, and kaempferol showed better correlation with RA inflammatory target genes such as PGR, PTGS1, PTGS2, NR3C2, TNFSF15, and CHRM2, respectively. The immune-inflammatory signaling pathways of the active ingredients for the treatment of RA are the TNF-α signaling pathway, Toll-like receptor signaling pathway, cell apoptosis, interleukin-17 signaling pathway, C-type lectin receptor signaling pathway, mitogen-associated protein kinase, etc. Molecular docking results suggested that mairin was the most appropriate natural TNFis. Conclusion: Our findings provide an essential role and basis for further immune-inflammatory studies into the molecular mechanisms of WP and TNFis development in RA.

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Design of novel JAK3 Inhibitors towards Rheumatoid Arthritis using molecular docking analysis.

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Design of novel JAK3 Inhibitors towards Rheumatoid Arthritis using molecular docking analysis.

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