Blood-brain barrier permeation

Blood-brain barrier permeation of 7, among other drugs, was predicted from its three-dimensional molecular structure by a computational method (0OJMC2204). The combination of molecular topological methods using 137 quinolones, including 7 provided an excellent tool for the design of new... 

Cabrera MA, Bermejo M, Perez M and Ramos R. TOPS-MODE approach for the prediction of blood-brain barrier permeation. J Pharm Sci 2004 93 1701-17. 

Ecker GF and Noe CR. In silico prediction models for blood-brain barrier permeation. Curr Med Chem 2004 11 1617-28. 

Narayanan R and Gunturi SB. In silico ADME modelling prediction models for blood-brain barrier permeation using a systematic variable selection method. Bioorg Med Chem 2005 13 3017-28. 

Subramanian G and Kitchen DB. Computational models to predict blood-brain barrier permeation and CNS activity. J Comput Aided Mol Des 2003 17 643-64. 

Eischer, H., Gottschlidi, R., Seelig, A. Blood-brain barrier permeation Molecular parameters governing passive diffusion, y. Membr. Biol. 1998, 165, 201-211. 

Luco, J. M., Marchevsky, E. QSAR smdies on blood-brain barrier permeation. Curr. Comput.-Aided Drug Des. 2006, 2, 31-55. 

Crivori, P., Crudani, G., Carrupt, P.-A., Testa, B. Predicting blood-brain barrier permeation from three-dimensional molecular structure. J. Med. Chem. 2000, 43, 2204-2216. 

Clark DE (2005) Computational prediction of blood-brain barrier permeation. In Doherty A (ed) Annual reports in medicinal chemistry. Elsevier, Oxford, p 413... 

Blood-Brain Barrier permeation (High, Low, Undecided)... 

Hutter MC (2003) Prediction of blood-brain barrier permeation using quantum chemically derived information. J Comput Aided Mol Des 17 415—433. 

Konovalov, D.A., Coomans, D., Deconinck, E., Vander Heyden, Y. Benchmarking of QSAR models for blood-brain barrier permeation. J. Chem. Inf. Model. 2007, 47,1648-56. 

D. E. Clark (2003). In silico prediction of blood-brain barrier permeation. Drug Discov. Today 8 927-933. 

On the other hand, PAMPA is a purely artificial method and PAMPA membranes do not reassemble real lipid bilayer structures as barriers for permeation but much thicker barriers. The thickness and material of the supporting PVDF filters also influences artificially the permeation of compounds depending on the lipophilicity of the compounds more than the thin polycarbonate filter does in CACo2 experiments. Also the best choice of membrane constituents for PAMPA experiments is still under investigation and it seems that it will depend a lot on the goal of the PAMPA experiment which membrane is used (e.g. blood brain barrier permeation or intestinal absorption). One has to take into account that PAMPA today is a summary term on a lot of different methods applied in different laboratories using different membrane constituents, sink conditions, permeation times etc., which makes inter laboratory comparison difficult. 

Preston, E., and Hynie, I. 1991. Transfer constants for blood-brain barrier permeation of the neuroexcitatory shellfish toxin,... 

A review of the literature will reveal that several QSPR equations have been developed to prediet PCs of drugs for use in PBPK models and many are suitable for a wide variety of ehemieals. It appears that the greatest deviations in predieted versus experimental measurements of PCs are largely due to an experimental uncertainty or misinterpretations of the data rather than incorrectness of the models. Strategies still need to be developed for other macromo-lecular binding (a -acid glycoprotein) and processes such as blood-brain barrier permeation and active transport but it appears that the methods thus developed are suitable for preliminary PBPK modeling. 

B. Testa, Predicting blood-brain barrier permeation from three-dimensional molecular structure,/. Med. Chem. 

VolSurfwas initially validated on oral absorption [16, 17] and blood-brain-barrier permeation [18] models (see belovi ). VolSurf has continued to be developed to improve in silico predictions for ADME properties, although its use has also been extended to receptor-based evaluation of binding affinity [19, 20], While other soft-ivare tools for ADME modeling are available (see, e.g., [21]), the MIF-based collection of sofhvare and models available from Molecular Discovery (MD) is both extensive and ivell validated by the private sector. Three programs from MD, VolSurf, MetaSite and Almond, are particularly suited for rapid evaluation of large compound sets [22] in connection ivith ADME/Tox related properties ... 

Adenot M, Lahana R. Blood-brain barrier permeation models Discriminating between potential CNS and non-CNS drags including P-glycoprotein substrates. J. Chem. Inf Comput. Sci. 2004 44 239-248. 

Figure 15.3 Novelty and margin detection applied to the 110 molecule test set for blood-brain barrier permeation (a) using 2D descriptors alone or (b) 2D and 3D descriptors.

Fischer, H., Gottschlich, R. and Seelig, A. (1998) Blood-brain barrier permeation molecular parameters governing passive... 

---