Pharmacophore filtering and 3D-QSAR in the discovery of new JAK2 inhibitors

Department of Bioinformatics, Alagappa University, Karaikudi 630003, Tamil Nadu, India.
Journal of molecular graphics & modelling (Impact Factor: 1.72). 07/2011; 30:186-97. DOI: 10.1016/j.jmgm.2011.07.004
Source: PubMed


Janus kinase 2 (JAK2) plays a crucial role in the patho-mechanism of cardiovascular pathologies, myeloproliferative disorders and many other diseases. Thus, effective JAK2 kinase inhibitors may be of significant therapeutic importance. In this study, a pharmacophore mapping studies were undertaken for a series of phenylaminopyrimidines derivatives. A five point pharmacophore with two hydrogen bond donors (D), two hydrogen bond acceptors (A) and one aromatic ring (R) as pharmacophoric features were developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R²=0.970 for training set compounds. The model generated showed excellent predictive power, with a correlation coefficient of Q²=0.822. The external validation indicated that our QSAR models possessed high predictive powers with r²(0) value of 0.999 and r²(m) value of 0.637 respectively. The model was then employed as 3D search query to screen against public compound libraries (Asinex, TOSLab, Maybride and Binding database) in-order to identify a new scaffold. We have identified thirteen distinct drug-like molecules binding to the JAK2. Interestingly, some of the compounds show activity against JAK2 by PASS biological activity prediction. Hence, these molecules could be potential selective inhibitors of JAK2 that can be experimentally validated and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for JAK2.

22 Reads
  • Source
    • "The survival score of this model was 3.728, and GH score for the same model was recorded as 0.748. Previously, Singh et al. (2011) were developed Pharmacophore-based 3D- QSAR model by using phenylaminopyrimidines derivatives , their results indicated that five features were important for the activity such as two hydrogen bond donors, two hydrogen bond acceptors, and one aromatic ring groups. In our work, the generated pharmacophore model shows similar features; additionally the model was validated based on the selectivity issues. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Janus-associated kinase 2 (JAK2) V617F mutation is believed to play a critical role in the pathogenesis of polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. The discovery of activating mutations associated with inhibition of cascade of events mediated by JAK2 target became an attractive approach for the treatment of myeloproliferative disorder. In this study, we performed a ligand-based pharmacophore modeling to explore the important chemical features of JAK2 inhibitors. The top ten hypotheses were generated based on 47 known inhibitors of JAK2 using PHASE module of Schrodinger software. The best pharmacophore hypothesis was found to be AADDR.212 which consists of two acceptors, two donors and one ring aromatic group. The selected model was validated by survival score, selectivity, and GH score. Two types of validation studies were done which includes potency validation by virtual screening against set of decoys, and selectivity validation by screening against set of inhibitors of JAK1, JAK2, JAK3, and Tyk2 (all tyrosine kinase family proteins). The selected model was utilized as a 3D query to screen against ZINC natural and chemical database, and subsequently the screened compounds were filtered by applying the Lipinski’s rule of five, ADME properties and molecular docking. Finally, fifteen compounds were obtained as novel virtual hits to inhibit the JAK2 enzyme
    Medicinal Chemistry Research 08/2014; 24(4). DOI:10.1007/s00044-014-1223-6 · 1.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Overweight and obesity are common health problems in modern society, particularly in developed countries. Excessive body mass has been linked to numerous diseases, such as cardiovascular diseases, diabetes, and cancer. Fat mass and obesity-associated protein (FTO) activity have direct impact on food intake and results in obesity. Inhibition of FTO activity may cause weight loss and reduce obese-linked health risks. We investigated the potential weight loss effects of traditional Chinese medicine (TCM), particularly by inhibiting FTO functions. Molecular docking was performed to screen TCM compounds from TCM Database@Taiwan ( Three candidates were identified that contained either a tetrahydropyridine group or potent electronegative phenol group in the structure scaffold. Molecular dynamics simulation analysis of the docking poses of each complex indicated stabilizing trends in the protein-ligand complex movements. In addition, the number of hydrogen bonds increased throughout the 20 ns simulation. These results suggest that these TCM candidates could be potential FTO inhibitors through competitive inhibition.
    Journal of biomolecular Structure & Dynamics 12/2011; 29(3):471-83. DOI:10.1080/07391102.2011.10507399 · 2.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 recep-tor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinical stud-ies on NK1-RAs have shown mixed results in reducing CINV risk. Most studies focused on the use of aprepitant (APR) and casopitant (CAS) in breast cancer patients receiving AC-type (doxorubicin and cyclophosphamide) chemotherapy. In this study, we compared the study design and clinical efficacies of these NK1-RAs in reducing CINV risk. Among the selected eight studies, 4 APR Randomized Controlled Trials (RCTs), 2 APR Observational Studies (OSs) and 2 CAS RCTs were identified. Patient-related characteristics such as the proportion of females (60.0% -100.0%), age (46.5 -59.5 years), histories of motion (5.6% -47.0% in NK1-RA arms) and morning sicknesses (14.2% -45.0% in NK1-RA arms) and types of antiemetic regimens; as well as chemotherapy-related characteristics such as the proportion of patients on AC chemotherapy (15.0% -100.0%) varied greatly. In terms of efficacies, both APR and CAS improved overall CR and vomiting in majority of the studies. None of the studies, however, demonstrated that NK1-RA could provide adequate nausea control. To conclude, NK1-RAs are effective in improving vomiting and overall CR, but not useful in controlling nausea or attaining CC, the ideal CINV endpoint. A shift in paradigm is needed for future CINV research. As healthcare providers continue to strive for optimum CINV control in their patients, we hope this review can help them make better informed clinical decisions.
    Journal of Cancer Therapy 02/2012; 3(1):90-102. DOI:10.4236/jct.2012.31012
Show more