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Field- and Gaussian-based 3D-QSAR studies on barbiturate analogs as MMP-9 inhibitors

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Abstract

Matrix metalloproteinase-9 (MMP-9) is one of the important enzymes belongs to gelatinase family and involved in multiple cellular processes including proliferation, angiogenesis, and metastasis. Various studies show that N-substituted homopiperazine barbiturates are promising and also selective for the MMP-9 inhibition. In this study, we selected and reported 49 barbiturate derivatives as inhibitors of MMP-9 and performed structure-based 3D-QSAR studies to elucidate the important structural features responsible for binding affinity. Crystal structure of MMP-9 complexed with barbiturate available in PDB was selected and performed quantum-polarized ligand docking for the reported inhibitors. Receptor-based alignment obtained from the docked poses were used for field- and Gaussian-based 3D-QSAR study. The results of both field and Gaussian models gave the good predictive correlation coefficient (test set) q 2 of 0. 77 and 0.85, and the conventional correlation coefficient (training set) r 2 of 0.845 and 0.928, respectively. The results of 3D-QSAR and docking studies validate each other and provided insight into the structural requirements for MMP-9 inhibition. The outcomes of the contour maps for both steric and Gaussian models results indicate that steric and hydrophobic interactions are major contributing factor for the activity and these findings will be useful to design the new inhibitors against MMP-9.

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Acknowledgments

I acknowledge Dr. Ravi Kumar, Schrodinger for his contribution and guidance to execute the total protocol involved in this study and I convey my gratitude to Mr. Raghu, Schrodinger for his support in completion of this study.

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Authors and Affiliations

  1. Department of Bioinformatics, SRM University, SRM Nagar, Kattankulathur- 603203, Kancheepuram District, Chennai, India

    Sukesh Kalva & Lilly M. Saleena

  2. College of Pharmacy, Madras Medical College, Chennai, 600003, India

    D. Vinod

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  1. Sukesh Kalva
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  2. D. Vinod
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  3. Lilly M. Saleena
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Correspondence to Lilly M. Saleena.

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Kalva, S., Vinod, D. & Saleena, L.M. Field- and Gaussian-based 3D-QSAR studies on barbiturate analogs as MMP-9 inhibitors. Med Chem Res 22, 5303–5313 (2013). https://doi.org/10.1007/s00044-013-0479-6

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