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Theoretical analysis of somatostatin receptor 5 with antagonists and agonists for the treatment of neuroendocrine tumors

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Abstract

We report on SSTR5 receptor modeling and its interaction with reported antagonist and agonist molecules. Modeling of the SSTR5 receptor was carried out using multiple templates with the aim of improving the precision of the generated models. The selective SSTR5 antagonists, agonists and native somatostatin SRIF-14 were employed to propose the binding site of SSTR5 and to identify the critical residues involved in the interaction of the receptor with other molecules. Residues Q2.63, D3.32, Q3.36, C186, Y7.34 and Y7.42 were found to be highly significant for their strong interaction with the receptor. SSTR5 antagonists were utilized to perform a 3D quantitative structure–activity relationship study. A comparative molecular field analysis (CoMFA) was conducted using two different alignment schemes, namely the ligand-based and receptor-based alignment methods. The best statistical results were obtained for ligand-based (\({q}^{2} = 0.454\), \({r}^{2}\) = 0.988, noc = 4) and receptor-guided methods (docked mode 1:\({q}^{2} = 0.530\), \({r}^{2} = 0.916\), noc = 5), (docked mode 2:\({q}^{2}\) = 0.555, \({r}^{2 }= 0.957\), noc = 5). Based on CoMFA contour maps, an electropositive substitution at \(\hbox {R}^{1}\), \(\hbox {R}^{2}\) and \(\hbox {R}^{4}\) position and bulky group at \(\hbox {R}^{4}\) position are important in enhancing molecular activity.

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Acknowledgements

This research was supported (in part) by Start-Up Research Grant for Young Scientist (SB/YS/LS-128/2013), funded by the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India. The authors thank SRM University for their continuous support and the facilities provided.

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  1. Department of Bioinformatics, School of Bioengineering, SRM University, SRM Nagar, Kattankulathur, Chennai, 603203, India

    Santhosh Kumar Nagarajan & Sathya Babu

  2. Molecular Modelling Lab, Department of Genetic Engineering, School of Bioengineering, SRM University, SRM Nagar, Kattankulathur, Chennai, 603203, India

    Santhosh Kumar Nagarajan, Sathya Babu & Thirumurthy Madhavan

  3. Department of Genetic Engineering, School of Bioengineering, SRM University, SRM Nagar, Kattankulathur, Chennai, 603203, India

    Thirumurthy Madhavan

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Nagarajan, S.K., Babu, S. & Madhavan, T. Theoretical analysis of somatostatin receptor 5 with antagonists and agonists for the treatment of neuroendocrine tumors. Mol Divers 21, 367–384 (2017). https://doi.org/10.1007/s11030-016-9722-7

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