Computational insights into rational design and virtual screening of pyrazolopyrimidine derivatives targeting Janus kinase 3 (JAK3)
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ABSTRACT:
SUBMITTER: Faris A
PROVIDER: S-EPMC11345245 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Janus kinase 3 (JAK3) is a non-receptor tyrosine kinases family of protein which is comprised of JAK1, JAK2, JAK3 and TYK2. It plays an important role in immune function and lymphoid development and it only resides in the hematopoietic system. Therefore, selective targeting JAK3 is a rational approach in developing new therapeutic molecule. In this study, about 116 JAK3 inhibitors were collected from the literature and were used to build four-point pharmacophore model using Phase (Schrodinger module). The statistically significant pharmacophore hypothesis of AAHR.92 with r2 value of 0.942 was used as 3D query to search against 3D database namely Zincpharmer. A total of 2, 27,483 compounds obtained as hit were subjected to high throughput virtual screening (HTVS module of Schrodinger). Among the hits, ten compounds with good G-score ranging from -12.96 to -11.18 with good binding energy to JAK3 were identified.
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Project description:Rheumatoid arthritis (RA) remains one of the most prevalent autoimmune diseases worldwide. Janus kinase 3 (JAK3) is an essential enzyme for treating autoimmune diseases, including RA. Molecular modeling techniques play a crucial role in the search for new drugs by reducing time delays. In this study, the 3D-QSAR approach is employed to predict new JAK3 inhibitors. Two robust models, both field-based with R2 = 0.93, R = 0.96, and Q2 = 87, and atom-based with R2 = 0.94, R = 0.97, and Q2 = 86, yielded good results by identifying groups that may readily direct their interaction. A reliable pharmacophore model, DHRRR1, was provided in this work to enable the clear characterization of chemical features, leading to the design of 13 inhibitors with their pIC50 values. The DHRRR1 model yielded a validation result with a ROC value of 0.87. Five promising inhibitors were selected for further study based on an ADMET analysis of their pharmacokinetic properties and covalent docking (CovDock). Compared to the FDA-approved drug tofacitinib, the pharmaceutical features, binding affinity and stability of the inhibitors were analyzed through CovDock, 300 ns molecular dynamics simulations, free energy binding calculations and ADMET predictions. The results show that the inhibitors have strong binding affinity, stability and favorable pharmaceutical properties. The newly predicted molecules, as JAK3 inhibitors for the treatment of RA, are promising candidates for use as drugs.
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Project description:BackgroundJanus kinase 3 (JAK3) is a member of the membrane-associated non-receptor tyrosine kinase protein family and is considered predominantly expressed in hematopoietic cells. We previously identified JAK3 as a differentially expressed gene in granulosa cells (GC) of bovine preovulatory follicles. The present study aimed to further investigate JAK3 regulation, to identify protein binding partners and better understand its mode of action in bovine reproductive cells.ResultsGC were obtained from small follicles (SF), dominant follicles at day 5 of the estrous cycle (DF), and ovulatory follicles, 24 h following hCG injection (OF). RT-PCR analyses showed greatest expression of JAK3 in GC of DF, while JAK3 expression was downregulated in OF (P < 0.0001). In addition, there was a 5- and 20-fold reduction of JAK3 steady-state mRNA levels in follicular walls, respectively at 12 and 24 hours post-hCG as compared to 0 h (P < 0.05). Similarly, JAK3 expression was downregulated by the endogenous LH surge. These results were confirmed in western blot analysis showing weakest JAK3 protein amounts in OF as compared to DF. Yeast two-hybrid screening of a DF-cDNA library resulted in the identification of JAK3 partners in GC that were confirmed by co-immunoprecipitation and included leptin receptor overlapping transcript-like 1 (LEPROTL1), inhibin beta A (INHBA) and cyclin-dependent kinase inhibitor 1B (CDKN1B). In functional studies using bovine endometrial cells, JAK3 increased phosphorylation of STAT3 and cell viability, while the addition of JANEX-1 inhibited JAK3 actions.ConclusionThese results support a physiologically relevant role of JAK3 in follicular development and provide insights into the mode of action and function of JAK3 in reproductive tissues.
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Project description:Predicting the bioactivity of peptides is an important challenge in drug development and peptide research. In this study, numerical descriptive vectors (NDVs) for peptide sequences were calculated based on the physicochemical properties of amino acids (AAs) and principal component analysis (PCA). The resulted NDV had the same length as the peptide sequence, so that each entry of NDV corresponded to one AA in the sequence. They were then applied to quantitative structure-activity relationship (QSAR) analysis of angiotensin-converting enzyme (ACE) inhibitor dipeptides, bitter-tasting dipeptides, and nonameric binding peptides of the human leukocyte antigens (HLA-A*0201). Multiple linear regression was used to construct the QSAR models. For each peptide set, a proper subset of physicochemical properties was chosen by the ant colony optimization algorithm. The leave-one-out cross-validation (q loo 2) values were 0.855, 0.936, and 0.642 and the root-mean-square errors (RMSEs) were 0.450, 0.149, and 0.461. Our results revealed that the new numerical descriptive vector can afford extensive characterization of peptide sequence so that it can be easily employed in peptide QSAR studies. Moreover, the proposed numerical descriptive vectors were able to determine hot spot residues in the peptides under study.
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Project description:The C-X-C chemokine receptor type 4 (CXCR4) is a potential therapeutic target for HIV infection, metastatic cancer, and inflammatory autoimmune diseases. In this study, we screened the ZINC chemical database for novel CXCR4 modulators through a series of in silico guided processes. After evaluating the screened compounds for their binding affinities to CXCR4 and inhibitory activities against the chemoattractant CXCL12, we identified a hit compound (ZINC 72372983) showing 100 nM affinity and 69% chemotaxis inhibition at the same concentration (100 nM). To increase the potency of our hit compound, we explored the protein-ligand interactions at an atomic level using molecular dynamics simulation which enabled us to design and synthesize a novel compound (Z7R) with nanomolar affinity (IC50 = 1.25 nM) and improved chemotaxis inhibition (78.5%). Z7R displays promising anti-inflammatory activity (50%) in a mouse edema model by blocking CXCR4-expressed leukocytes, being supported by our immunohistochemistry study.
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Project description:Due to the synergic relationship between medical chemistry, bioinformatics and molecular simulation, the development of new accurate computational tools for small molecules drug design has been rising over the last years. The main result is the increased number of publications where computational techniques such as molecular docking, de novo design as well as virtual screening have been used to estimate the binding mode, site and energy of novel small molecules. In this work I review some tools, which enable the study of biological systems at the atomistic level, providing relevant information and thereby, enhancing the process of rational drug design.
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Project description:Amyloid β (Aβ) sheets aggregations is the main reason of Alzheimer disease. The interacting areas between monomers are residue number 38 to 42. Inhibition of interaction between Aβ molecules prevents plaque formation. In the present study, we have performed a high-throughput virtual screening among ZINC database and top 1000 hits were checked again regarding binding affinity by AutoDock software. Top 4 successive second step screening hits was considered for drug design purpose against aggregation site of Aβ molecules. The toxicity and pharmacological properties of new designed ligands was assessed by PROTOX and FAFdrugs3 webservers. Several steps of modifications performed in the structures of hit#1 and hit#2 and finally new designed ligand based on hit 1, 1-RD-3 (3-[(Z)-6-Hydroxy-4-{[5-(2-methoxyethyl)-6-methyltetrahydro-2H-pyran-2-yl]methyl}-1-methyl-3-hexenyloxy]tetrahydro-2Hpyran- 4-ol) and a designed ligand based on hit 2, 2-RD-2 (6-(Hydroxymethyl)-4-{5-hydroxy-6-methyl-4-[(3- methylcyclohexyl)methyl]tetrahydro-2H-pyran-2-yloxy}tetrahydro-2H-pyran-2,3,5-triol) could successfully pass pharmacological filters. The LD50 of 37000 mg/kg for 1-RD-3 and 2000 mg/kg for 2-RD-2 indicates that the designed ligands can be considered as new candidates for anti Aβ aggregation to treat Alzheimer's disease. Interestingly, after performing several modification steps still a considerable binding affinity of -9.3 kcal/mol for 1-RD-3 and -9.8 kcal/mol for 2-RD-2 still remained. Theoretically, the new designed molecules can reduce the deposition of Aβ in the cerebral cortex and as the results the Alzheimer symptoms could be decreased.
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