Pharmacophore model generation and 3D-QSAR analysis of N -acyl and N -aroylpyrazolines for enzymatic and cellular B-Raf
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Med Chem Res DOI 10.1007/s00044-012-0210-z
ORIGINAL RESEARCH
Pharmacophore model generation and 3D-QSAR analysis of N-acyl and N-aroylpyrazolines for enzymatic and cellular B-Raf kinase inhibition Omprakash Tanwar • Akranth Marella • Sandeep Shrivastava • M. Mumtaz Alam Mymoona Akhtar
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Received: 2 May 2011 / Accepted: 20 August 2012 Ó Springer Science+Business Media, LLC 2012
Abstract A successful 3D-QSAR study has been performed for amino-substituted N-acyl and N-aroylpyrazolines as B-Raf kinase inhibitors by means of a common five-point pharmacophore model. In this study, highly predictive 3DQSAR models have been developed for B-Raf kinase inhibition and pERK inhibition using AADRR-2 and AADRR-6 hypothesis, respectively. The best models showed statistically outstanding values of 0.97, 0.95 and 0.91, 0.87 for r2 and q2 for AADRR-2 and AADRR-6 hypothesis, respectively. The validation of the PHASE model was done by dividing the dataset into training and test set. From the QSAR model, it can implicated that electron-withdrawing and hydrophobic groups are not advantageous for both enzymatic and cellular activities. However, H-bond donor characteristic is favorable for cellular inhibition and unfavorable for enzymatic inhibition. Based on the findings of the 3DQSAR study, novel and promising compounds for B-Raf kinase inhibition can be synthesized. Keywords 3D-QSAR Pharmacophore PHASE Phosphodiesterases N-acyl and N-aroylpyrazolines Schro¨dinger Introduction Cancer is a major concern of research scientists as it is the most important cause of deaths worldwide. So there is a
O. Tanwar A. Marella S. Shrivastava M. Mumtaz Alam M. Akhtar (&) Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India e-mail: [email protected]; [email protected]
compelling need to develop new drugs to treat this lifethreatening disease. Targeting enzymes involved in signal transduction pathways is an important approach that has received the attention of medicinal chemists. Raf, a serine/ threonine protein kinase is a part of the mitogen-activated protein kinase (MAPK) signal transduction cascade (Robinson and Cobb, 1997). The MAPK signaling path consists of the Ras/Raf/MEK/ERK signal transduction cascade which regulates cellular growth and proliferation and is found to be mutated in many types of cancer (Davies et al., 2002). The uncontrolled proliferation of tumor cells resulted from mutation of glutamic acid to valine at amino acid position 600 (V600E) in the isoform B-Raf resulting in the constitutive activation of the MAP kinase cascade. The suppression of B-Raf (V600E) in human melanoma cells leads to arresting of MAP kinase signaling cascade, resulting in apoptosis in vitro, and blocks tumor growth in vivo, thereby validating BRAF as a therapeutic target in human cancer (Hingorani et al, 2003; Karasarides et al, 2004; Hoeflich et al, 2006) Till date there are number of B-Raf kinase inhibitors that are available suc
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