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Comparative Molecular Field Analysis of Pyrrolopyrimidines as LRRK2 Kinase Inhibitors
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 Title & Authors
Comparative Molecular Field Analysis of Pyrrolopyrimidines as LRRK2 Kinase Inhibitors
Balupuri, Anand; Balasubramanian, Pavithra K.; Cho, Seung Joo;
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 Abstract
Leucine rich repeat kinase 2 (LRRK2) is a highly promising target for Parkinson`s disease (PD) that affects millions of people worldwide. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of pyrrolopyrimidine-based selective LRRK2 kinase inhibitors. This study was performed to rationalize the structural requirements responsible for the inhibitory activity of these compounds. A reliable 3D-QSAR model was developed using comparative molecular field analysis (CoMFA) technique. The model produced statistically acceptable results with a cross-validated correlation coefficient () of 0.539 and a non-cross-validated correlation coefficient () of 0.871. Robustness of the model was further evaluated by bootstrapping and progressive scrambling analysis. This work could assist in designing more potent LRRK2 inhibitors.
 Keywords
Parkinson`s Disease;LRRK2 Kinase;Pyrrolopyrimidines;3D-QSAR;CoMFA;
 Language
English
 Cited by
1.
Molecular Docking Studies of p21-Activated Kinase-1 (PAK1) Inhibitors,;;;

조선자연과학논문집, 2016. vol.9. 3, pp.161-165 crossref(new window)
1.
Molecular Docking Studies of p21-Activated Kinase-1 (PAK1) Inhibitors, Journal of the Chosun Natural Science, 2016, 9, 3, 161  crossref(new windwow)
 References
1.
K.-L. Lim and C.-W. Zhang, "Molecular events underlying Parkinson's disease - an interwoven tapestry", Frontiers in Neurology, Vol. 4, 2013.

2.
C. Labbe and O. A. Ross, "Association studies of sporadic Parkinson's disease in the genomic era", Curr. Genomics, Vol. 15, pp. 2-10, 2014. crossref(new window)

3.
S. Lubbe and H. R. Morris, "Recent advances in Parkinson's disease genetics", J. Neurol., Vol. 261, pp. 259-266, 2014. crossref(new window)

4.
I. Marin, "The Parkinson disease gene LRRK2: evolutionary and structural insights", Mol. Biol. Evol., Vol. 23, pp 2423-2433, 2006. crossref(new window)

5.
A. R. Esteves, R. H. Swedlow, and S. M. Cardoso, "LRRK2, a puzzling protein: insights into Parkinson's disease pathogenesis", Exp. Neurol., Vol. 261, pp. 206-216, 2014. crossref(new window)

6.
T. T. Wager, X. Hou, P. R. Verhoest, and A. Villalobos, "Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties", ACS Chem. Neurosci., Vol. 1, pp. 435-449, 2010. crossref(new window)

7.
J. L. Henderson, B. L. Kormos, M. M. Hayward, K. J. Coffman, J. Jasti, R. G. Kurumbail, T. T. Wager, P. R. Verhoest, G. S. Noell, Y. Chen, E. Needle, Z. Berger, S. J. Steyn, C. Houle, W. D. Hirst, and P. Galatsis, "Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor", J. Med. Chem., Vol. 58, pp 419-432, 2015. crossref(new window)

8.
A. Balupuri and S. J. Cho, "Exploration of the binding mode of indole derivatives as potent HIV-1 inhibitors using molecular docking simulations", J. Chosun Natural Sci., Vol. 6, pp. 138-142, 2013. crossref(new window)

9.
A. Balupuri, P. K. Balasubramanian, and S. J. Cho, "A CoMFA study of glycogen synthase kinase 3 inhibitors", J. Chosun Natural Sci., Vol. 8, pp. 40-47, 2015. crossref(new window)

10.
A. Balupuri, P. K. Balasubramanian, and S. J. Cho, "A CoMFA study of quinazoline-based anticancer agents", J. Chosun Natural Sci., Vol. 8, pp. 214-220, 2015. crossref(new window)

11.
P. K. Balasubramanian, A. Balupuri, and S. J. Cho, "A CoMFA study of phenoxypyridine-based JNK3 inhibitors using various partial charge schemes", J. Chosun Natural Sci., Vol. 7, pp. 45-49, 2014. crossref(new window)

12.
P. K. Balasubramanian, A. Balupuri, and S. J. Cho, "Ligand-based CoMFA study on pyridylpyrazolopyridine derivatives as $PKC{\theta}$ kinase inhibitors", J. Chosun Natural Sci., Vol. 7, pp. 253-259, 2014. crossref(new window)

13.
SYBYLx2.1, Tripos International, 1699 South Hanley Road, St. Louis, Missouri, 63144, USA.

14.
R. D. Cramer, D. E. Patterson, and J. D. Bunce, "Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins", J. Am. Chem. Soc., Vol. 110, pp. 5959-5967, 1988. crossref(new window)

15.
S. Wold, A. Ruhe, H. Wold, and W. J. Dunn, III, "The collinearity problem in linear regression. The partial least squares (PLS) approach to generalized inverses", SIAM Journal on Scientific and Statistical Computing, Vol. 5, pp 735-743, 1984. crossref(new window)

16.
R. D. Cramer, J. D. Bunce, D. E. Patterson, and I. E. Frank, "Crossvalidation, bootstrapping, and partial least squares compared with multiple regression in conventional QSAR studies", Quantitative Structure-Activity Relationships, Vol. 7, pp. 18-25, 1988. crossref(new window)