Developing Database of Inhibitors against JNK Isotypes for analyzing Specificity of Fragments against these Targets

Abstract

The JNK inhibitors against Alzhmeir disease (AD) should be efficient when they modulate the JNK activity for treatment of AD without affecting other cells. Though some inhibitors were reported but using for them for treatment lead to side-effects and toxicity. Further, the current JNK inhibitors inhibit all JNKs because of highly similarity between the isotypes which may lead to further complications. Thus, we need specific JNK inhibitors that provide both cell type and signal specificity. Present study is intent to develope a database of inhibitors (AlzID) active against AD promising drug targets JNK isotypes collected from published literature. This database contains over 650 molecules and their activity data (IC50 values) against three JNK enzymes. Optimized 3D geometries are provided to allow virtual screening. Geometry of each inhibitor is optimized using B3LYP (Becke‟s Lee Yang and Parr correlation) approach. The inhibitors were annotated with their molecular properties such molecular weight, LogD, LogP, asymmetric atoms, number of rotatable bonds etc. Other information such as SMILES, IUPAC name, etc. were also provided. To determine common and specific fragments, each inhibtors were fragmented on the basis of Bemis Murcko method i.e. ring, side-chain, linker and framework (to find which fragment exist and how frequent are they). We identified the fragments that were occurring more than random in a dataset. Based on the frequencies of fragments in dataset, we identified common and unique fragments for JNK isotypes. The inhibitors data were provided with several common file formats including SMILES, SDF and mol2. A molecular drawing interface (JME) and R-Package „rcdk‟ was incorporated into the database to facilitate searching of molecules on the basis of similarity. Text-based query is also available. Access and retrieval of data through similarity based searching and text-based method are available. This database also allow user to upload/draw desired molecules for searching. User can also get library of molecules for virtual screening that are specific against a particular JNK isotype.