Molecular docking and 3D-QSAR studies on inhibitors of DNA damage signaling enzyme human PARP-1

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) operates in a DNA damage signaling network. Molecular docking and three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on human PARP-1 inhibitors. Docked conformation obtained for each molecule was used as such for 3D-QSAR analysis. Molecules were divided into a training set and a test set randomly in four different ways, partial least square analysis was performed to obtain QSAR models using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Derived models showed good statistical reliability that is evident from their r², q²_loo and r²_pred values. To obtain a consensus for predictive ability from all the models, average regression coefficient r²_avg was calculated. CoMFA and CoMSIA models showed a value of 0.930 and 0.936, respectively. Information obtained from the best 3D-QSAR model was applied for optimization of lead molecule and design of novel potential inhibitors.

Keywords::

• Poly (ADP-ribose) polymerase -1 (PARP-1)
• DNA damage signaling
• 3D-QSAR (3 dimensional-quantitative structure activity relationship)
• CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis)
• Quinazolinone
• Phthalazinone

Acknowledgments

We gratefully acknowledge support for this research from Council of Scientific and Industrial Research (Project No. 01/(2436)/10/EMR-II), Department of Science and Technology, New Delhi, India, University Grants Commission, New Delhi, India and Department of chemistry, Nizam College, Hyderabad, India. We also acknowledge Schrödinger Inc. for GLIDE software, Tripos Inc. for SYBYLX-1.2.

Declaration of interest

The authors report no conflicts of interest.