Pharmacophore filtering and 3D-QSAR in the discovery of new JAK2 inhibitors
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.
Available from: Raja Natesan Sella
- "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. "
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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
- "Prime/MM-GBSA is used to predict the free energy of binding for set of ligands to receptor. The binding free energy (G bind ) was calculated based on published papers (Dhanachandra Singh et al., 2011; Mobley et al., 2006; Ge and Roux, 2010; Hou et al., 2011). "
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ABSTRACT: The outbreak of influenza virus A (2009) subtype H1N1 and H5N1 virus infection is an important issue since it affects both human and animal health. The crystal structure of H1N1 was recently solved. Oseltamivir and Zanamivir are the drugs which are broadly used for the treatment of H5N1 and H1N1 infection but many studies reported that these drugs show resistance to these types of infections. The main goal of the present study is to understand the molecular level interactions of neuraminidase-inhibitor. We carried out two different molecular dynamics simulation calculations of neuraminidase protein in complex with Oseltamivir and Zanamivir. The important interaction between protein and ligand were broadly studied from the molecular dynamics simulation trajectories of 10 ns. The molecular docking, molecular dynamics and binding energy calculation results revealed that the 150-cavitiy in the active site may play an important role in binding of drugs. Free energy calculation reveals that electrostatic interaction is more favorable for Oseltamivir interaction with H1N1 and van der Waals interaction is more favorable for H5N1, whereas Zanamivir favors the electrostatic interaction in both the strains (H1N1 and H5N1). Energy-optimized pharmacophore mapping was performed using Oseltamivir drug. Based on the results, we propose the pharmacophore features that must be present in an inhibitor of H1N1. The resulting pharmacophore model contained two hydrogen-bond acceptor and two hydrogen-bond donor sites. Using these pharmacophore features, we screened a large public library of compounds (ChemBridge and Binding Database) to find a potential ligand that could inhibit the H1N1 protein. Here, we report the best five compounds based on their docking scores. The current research will pave the way to find potent neuraminidase inhibitors against H1N1 (2009) strain.
International Journal of Computational Biology and Drug Design 01/2014;
Available from: ir.cmu.edu.tw
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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 (http://tcm.cmu.edu.tw). 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
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