Novel Fragment‐Based QSAR Modeling and Combinatorial Design of Pyrazole‐Derived CRK3 Inhibitors as Potent Antileishmanials. (14th May 2014)

• Record Type: Journal Article
• Authors: Goyal, Sukriti; Dhanjal, Jaspreet K.; Tyagi, Chetna; Goyal, Manisha; Grover, Abhinav
• Is Part Of: Chemical biology & drug design. Volume 84:Number 1(2014:Jul.)
• Page Start: 54
• Page End: 62
• Publication Date: 2014-05-14
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12290
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12290-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The CRK3 cyclin‐dependent kinase of <italic>Leishmania</italic> plays an important role in regulating the cell‐cycle progression at the G2/M phase checkpoint transition, proliferation, and viability inside the host macrophage. In this study, a novel fragment‐based QSAR model has been developed using 22 pyrazole‐derived compounds exhibiting inhibitory activity against <italic>Leishmanial </italic>CRK3. Unlike other QSAR methods, this fragment‐based method gives flexibility to study the relationship between molecular fragments of interest and their contribution for the variation in the biological response by evaluating cross‐term fragment descriptors. Based on the fragment‐based QSAR model, a combinatorial library was generated, and top two compounds were reported after predicting their activity. The QSAR model showed satisfactory statistical parameters for the data set (<italic>r</italic><sup>2</sup> = 0.8752, <italic>q</italic><sup>2</sup> = 0.6690, <italic>F</italic>‐ratio = 30.37, and pred_<italic>r</italic><sup>2</sup> = 0.8632) with four descriptors describing the nature of substituent groups and the environment of the substitution site. Evaluation of the model implied that electron‐rich substitution at R<sub>1</sub> position improves the inhibitory activity, while decline in inhibitory activity was observed in presence of nitrogen at R<sub>2</sub> position. The analysis carried out in this study provides a substantial basis for consideration of the designed pyrazole‐based leads as potent antileishmanial drugs.</p> </abstract>