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J Mol Graph Model. 2013 Feb;39:165-75. doi: 10.1016/j.jmgm.2012.11.011. Epub 2012 Dec 8.

Designing of new multi-targeted inhibitors of spleen tyrosine kinase (Syk) and zeta-associated protein of 70kDa (ZAP-70) using hierarchical virtual screening protocol.

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1
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.

Abstract

In the present study, diverse inhibitor molecules of two protein tyrosine kinases i.e. Syk and ZAP-70 were considered for the pharmacophore and docking analyses to design new multi-targeted agents for these enzymes. These enzymes are non-receptor protein tyrosine kinases and both are expressed mainly in B and T-lymphocytes where they play a crucial role in immune signaling. The role of these two enzymes in inflammatory and autoimmune diseases makes them potential therapeutic targets for the designing of new multi-targeted agents to combat disease conditions associated with them. The pharmacophore models were developed for Syk and ZAP-70 inhibitors using PHASE module of Schrödinger software. The generated pharmacophore models for both enzymes were clustered and top five models for each target were selected on the basis of survival minus inactive score that were subsequently used for the 3D-QSAR analysis. The best model for Syk (ADHR.45-5) and ZAP-70 (AADRR.265-3) were selected corresponding to highest value of Q(2). Both models were employed for the screening of a PHASE database of approximately 1.5 million compounds, subsequently the retrieved hits were screened employing docking simulations with Syk and ZAP-70 proteins. Finally, the screened compounds having structural features of both pharmacophore models and displaying essential interactions with both proteins were investigated for ADME properties. Thus, the new leads obtained in this way would show inhibitory activity against Syk and ZAP-70, and may serve as novel therapeutic agents for the treatment of inflammatory disorders.

PMID:
23280414
DOI:
10.1016/j.jmgm.2012.11.011
[Indexed for MEDLINE]
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