3D-QSAR and Docking Studies on Pyrimidine Derivatives as CSF-1R Inhibitors

Author(s): Ya-ting Deng, Jun-wei Wang, Han Chu, Juan Wang, Yong Hu, Yong lin, Mao Shu, Zhi-hua Lin*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 3 , 2020

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Graphical Abstract:


Background: Colony Stimulating Factor-1 Receptor (CSF-1R) is associated with malignancy, invasiveness and poor prognosis of tumors, and pyrimidine derivatives are considered as a novel class of CSF-1R inhibitor.

Methods: To explore the relationship between the structures of substituted pyrimidine derivatives and their inhibitory activities against CSF-1R, CoMFA and CoMSIA analyses, and molecular docking studies were performed on a dataset of forty-four compounds.

Results: We found in CoMFA model including steric and electrostatic fields for the training set, the cross-validated q2 value was 0.617 and the non-cross-validated r2 value was 0.983. While, the crossvalidated q2 value was 0.637 and the non-cross-validated r2 value was 0.984 in CoMSIA Model which include steric, electrostatic and hydrophobic fields. 3D equipotential maps generated from CoMFA and CoMSIA along with the docking binding structures provided enough information about the structural requirements for better activity.

Conclusion: The data generated from the present study helped us to predict the activity of new inhibitors and further design some novel and potent CSF-1R inhibitors.

Keywords: CSF-1R, inhibitor, 3D-QSAR, molecular docking, anti-tumor, pyrimidine derivatives.

Garcia, S.; Hartkamp, L.M.; Malvar-Fernandez, B.; van Es, I.E.; Lin, H.; Wong, J.; Long, L.; Zanghi, J.A.; Rankin, A.L.; Masteller, E.L.; Wong, B.R.; Radstake, T.R.; Tak, P.P.; Reedquist, K.A. Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis. Arthritis Res. Ther., 2016, 18(1), 75.
[http://dx.doi.org/10.1186/s13075-016-0973-6] [PMID: 27036883]
Wang, X.L.; Jiang, J.T.; Wu, C.P. Prognostic significance of tumor-associated macrophage infiltration in gastric cancer: A meta-analysis. Genet. Mol. Res., 2016, 15(4)
[http://dx.doi.org/10.4238/gmr15049040] [PMID: 27966749]
Kai, K.; Iwamoto, T.; Zhang, D. CSF-1/CSF-1R axis is associated with epithelial/mesenchymal hybrid phenotype in epithelial-like inflammatory breast cancer. Sci. Rep., 2018, 8(1), 9427-9436.
Baghdadi, M.; Endo, H.; Takano, A.; Ishikawa, K.; Kameda, Y.; Wada, H.; Miyagi, Y.; Yokose, T.; Ito, H.; Nakayama, H.; Daigo, Y.; Suzuki, N.; Seino, K.I. High co-expression of IL-34 and M-CSF correlates with tumor progression and poor survival in lung cancers. Sci. Rep., 2018, 8(1), 418.
[http://dx.doi.org/10.1038/s41598-017-18796-8] [PMID: 29323162]
Cunyat, F.; Rainho, J.N.; West, B. CSF-1R antagonists sensitize HIV-1-infected macrophages to TRAIL-mediated killing. J. Virol., 2016, 90(14), 6255-6262.
[http://dx.doi.org/10.1128/JVI.00231-16] [PMID: 27122585]
Xun, Q.; Zhang, Z.; Luo, J.; Tong, L.; Huang, M.; Wang, Z.; Zou, J.; Liu, Y.; Xu, Y.; Xie, H.; Tu, Z.C.; Lu, X.; Ding, K. Design, synthesis, and structure-activity relationship study of 2-oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as new colony stimulating factor 1 receptor (CSF1R) kinase inhibitors. J. Med. Chem., 2018, 61(6), 2353-2371.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01612] [PMID: 29499108]
Kim, K H Comparative molecular field analysis (CoMFA)[J]. 1995.
Klebe, G. Comparative molecular similarity indices analysis: CoMSIA. Perspect. Drug Discov. Des., 1998, 12-14(10), 87-104.
Gan, X.; Hu, D.; Li, P.; Wu, J.; Chen, X.; Xue, W.; Song, B. Design, synthesis, antiviral activity and three-dimensional quantitative structure-activity relationship study of novel 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety. Pest Manag. Sci., 2016, 72(3), 534-543.
[http://dx.doi.org/10.1002/ps.4018] [PMID: 25847602]
Purcell, W.P.; Singer, J.A. A brief review and table of semiempirical parameters used in the Hueckel molecular orbital method. J. Chem. Eng. Data, 1967, 12(2), 235-246.
Guttikonda, V.; Raavi, D.; Maadwar, S.K.; Gade, D.R. Molecular insights of benzodipyrazole as CDK2 inhibitors: Combined molecular docking, molecular dynamics, and 3D QSAR studies. J. Recept. Signal Transduct. Res., 2015, 35(5), 439-449.
[http://dx.doi.org/10.3109/10799893.2015.1018433] [PMID: 25902329]
Nikolic, K.; Mavridis, L.; Djikic, T.; Vucicevic, J.; Agbaba, D.; Yelekci, K.; Mitchell, J.B. Drug design for CNS diseases: Polypharmacological profiling of compounds using cheminformatic, 3D-QSAR and virtual screening methodologies. Front. Neurosci., 2016, 10, 265.
[http://dx.doi.org/10.3389/fnins.2016.00265] [PMID: 27375423]
Verma, J.; Khedkar, V.M.; Coutinho, E.C. 3D-QSAR in drug design--a review. Curr. Top. Med. Chem., 2010, 10(1), 95-115.
[http://dx.doi.org/10.2174/156802610790232260] [PMID: 19929826]
Klebe, G.; Abraham, U. Comparative molecular similarity index analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries. J. Comput. Aided Mol. Des., 1999, 13(1), 1-10.
[http://dx.doi.org/10.1023/A:1008047919606] [PMID: 10087495]
Akamatsu, M. Current state and perspectives of 3D-QSAR. Curr. Top. Med. Chem., 2002, 2(12), 1381-1394.
[PMID: 12470286]
Perriello, G.; Pampanelli, S.; Del Sindaco, P.; Lalli, C.; Ciofetta, M.; Volpi, E.; Santeusanio, F.; Brunetti, P.; Bolli, G.B. Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM. Diabetes, 1997, 46(6), 1010-1016.
[http://dx.doi.org/10.2337/diab.46.6.1010] [PMID: 9166673]
Huang, H.; Hutta, D.A.; Rinker, J.M.; Hu, H.; Parsons, W.H.; Schubert, C.; DesJarlais, R.L.; Crysler, C.S.; Chaikin, M.A.; Donatelli, R.R.; Chen, Y.; Cheng, D.; Zhou, Z.; Yurkow, E.; Manthey, C.L.; Player, M.R. Pyrido[2,3-d]pyrimidin-5-ones: A novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors. J. Med. Chem., 2009, 52(4), 1081-1099.
[http://dx.doi.org/10.1021/jm801406h] [PMID: 19193011]

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Year: 2020
Page: [341 - 355]
Pages: 15
DOI: 10.2174/1570180816666190329224946
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