Validation of topochemical models for the prediction of permeability through the blood-brain barrier

Open access

Validation of topochemical models for the prediction of permeability through the blood-brain barrier

Recently published topochemical models for permeability through the blood-brain barrier were validated and cross-validated in the present study. Five models based on three topochemical indices, Wiener's topochemical index - a distance-based topochemical descriptor, molecular connectivity topochemical index - an adjacency-based topochemical descriptor and eccentric connectivity topochemical index - an adjacency-cum-distance based topochemical descriptor, for permeability of structurally and chemically diverse molecules through blood-brain barrier were used in the present investigation. A data set comprising 62 structurally and chemically diverse compounds was selected. This data set was divided into two sets of 31 compounds each - one to serve as the validation set and other as the cross-validation set. The values of all the three-topochemical indices in the original as well as in the normalized form for each of the 31 compounds of the validation set were computed using an in-house computer program. Resultant data was analyzed and each compound was assigned a permeability characteristic using topochemical models, which was then compared with the reported permeability through the blood-brain barrier. Accuracy of prediction of these models was calculated. The same procedure was similarly followed for the cross-validation set. Studies revealed accuracy of prediction of the order of 70-80% during validation. Surprisingly, very high predictability of the order of 77-91% was observed during cross-validation. High predictability observed during validation as well as cross-validation authenticates topochemical models for prediction of permeability through the blood-brain barrier.

K. Rose, L. H. Hall and L. B. Kier, Modeling blood-brain barrier partitioning using the electrotopological state, J. Chem. Inf. Comput. Sci.42 (2002) 651-666; DOI: 10.121/ci010127n.

D. E. Clark, Rapid calculation of polar molecular surface and its application to the prediction of transport phenomena. 2. Prediction of blood-brain barrier penetration, J. Pharm. Sci.88 (1999) 815-821; DOI:10.1021/js980402t.

J. M. Luco, Prediction of the brain-blood distribution of a large set of drugs from structurally derived descriptors using partial least-square (PLS) modeling, J. Chem. Inf. Comput. Sci.39 (1999) 396-404; DOI: 10.121/ci980411n.

G. M. Keseru and L. Molnar, High-throughput prediction of blood-brain partitioning: A thermodynamic approach, J. Chem. Inf. Comput. Sci.41 (2001) 120-128; DOI: 10.1021/ci000043z.

X.-L. Ma, C. Chen and J. Yang, Predictive model of blood-brain barrier penetration of organic compounds, Acta Pharmacol. Sin.26 (2005) 500-512; DOI: 10.1111/j.1745-7254.2005.00068.x.

R. Liu, H. Sun and S.-S. So, Development of quantitative structure-property relationship models for early ADME evaluation in drug discovery. 2. Blood-brain barrier penetration, J. Chem. Inf. Comput. Sci.41 (2001) 1623-1632; DOI: 10.1021/ci010290i.

J. Kelder, P. D. J. Grootenhuis, D. M. Bayada, L. P. C. Delbressine and J.-P. Ploemen, Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs, Pharm. Res.16 (1999) 1514-1519; DOI: 10.1023/A:1015040217741.

N. J. Abbott, L. Rönnbäck and E. Hansson, Astrocyte - endothelial interactions at the blood-brain barrier, Nat. Rev. Neurosci.7 (2006) 41-53; DOI: 10.1038/nrn1824.

F. Lombardo, J. F. Blake and W. J. Curatolo, Computation of brain-blood partitioning of organic solutes via free energy calculations, J. Med. Chem.39 (1996) 4750-4755; DOI: 10.1021/jm960163r.

P. Crivori, G. Cruciani, P.-A. Carrupt and B. Testa, Predicting blood-brain barrier permeation using three-dimensional molecular structure, J. Med. Chem.43 (2000) 2204-2216; DOI: 10.1021/ jm990968.

R. Kunal, Topological descriptors in drug design and modeling studies, Mol. Div.8 (2004) 321-323; DOI: 10.1023/B:MODI.0000047519.35591.b7.

S. C. Basak, S. Bertelsen and G. Grunwald, Application of graph theoretical parameters in quantifying molecular similarity and structure-activity studies, J. Chem. Inf. Comput. Sci.34 (1994) 270-276; DOI: 10.1021/ci00018a007.

B. D. Gute and S. C. Basak, Predicting acute toxicity (LC50) of benzene derivatives using theoretical molecular descriptors: A hierarchical QSAR approach, SAR QSAR Environ. Res.7 (1997) 117-131; DOI: 10.1080/10629369708039127.

H. Dureja and A. K. Madan, Topochemical models for prediction of permeability through blood-brain barrier, Int. J. Pharm.323 (2006) 27-33; DOI: 10.1016/j/ijpharm.2006.05.042.

S. Bajaj, S. S. Sambi and A. K. Madan, Predicting anti-HIV activity of phenethylthiazolethiourea (PETT) analogs: computational approach using Wiener's topochemical index, J. Mol. Struct. (THEOCHEM)684 (2004) 197-203; DOI: 10.1016/j.theochem.2004.01.052.

H. Wiener, Correlation of heat of isomerization and difference in heat of vaporization of isomers among paraffin hydrocarbons, J. Am. Chem. Soc.69 (1947) 2636-2638; DOI: 10.1021/ja01203a022.

A. Goel and A. K. Madan, Structure-activity study on anti-inflammatory pyrazole carboxylic acid hydrazide analogs using molecular connectivity indices, J. Chem. Inf. Comput. Sci.35 (1995) 510-514; DOI: 10.1021/ci00025a019.

H. Dureja and A. K. Madan, Topochemical models for prediction of cyclin-dependent kinase 2 inhibitory activity of indole-2-ones, J. Mol. Mod.11 (2005) 525-531; DOI: 10.1007/s00894-005-0276-3.

M. Randic, On characterization of molecular branching, J. Am. Chem. Soc.97 (1975) 6609-6615; DOI: 10.1021/ja00856a001.

V. Kumar, S. Sardana and A. K. Madan, Predicting anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-ones: computational approach using reformed eccentric connectivity index, J. Mol. Mod.10 (2004) 399-407; DOI: 10.1007/s00894-004-0215-8.

V. Sharma, R. Goswami and A. K. Madan, Eccentric connectivity index: a novel highly discriminating topological descriptor for structure property and structure activity studies, J. Chem. Inf. Comput. Sci.37 (1997) 273-282; DOI: 10.1021/ci960079h.

M. Iyer, R. Mishra, Y. Han and A. J. Hopfinger, Predicting blood-brain barrier partitioning of organic molecules using membrane-interaction QSAR analysis, Pharm. Res.19 (2002) 1611-1621; DOI: 10.1023/A:1020792909928.

M. H. Abraham, K. Takacs-Novak and R. C. Mitchell, On the partition of ampholytes: Application to blood-brain distribution, J. Pharm. Sci.86 (1997) 310-315; DOI: 10.1021/js960328j.

M. C. Hutter, Prediction of blood-brain barrier permeation using quantum chemically derived information, J. Computer-Aided Mol. Des.17 (2003) 415-433; DOI: 10.1023/A:1027359714663.

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

Journal Information

IMPACT FACTOR 2017: 1.071
5-year IMPACT FACTOR: 1.623

CiteScore 2017: 1.46

SCImago Journal Rank (SJR) 2017: 0.362
Source Normalized Impact per Paper (SNIP) 2017: 0.642


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 142 142 14
PDF Downloads 44 44 5