Elucidation of the reaction site of Calyxamines A and B in acetylcholinesterase and desing of a drug derived from calyxamines A and B, potentially active against Alzheimer´s disease through computational nanotechnology
Keywords:
Nanotechnology, calyxamines, docking, intelligent drug desing, acetylcholinesterase, pharmacophoric, propertiesAbstract
Abstract
The aim of this work was to design a new compound that successfully inhibits Acetylcholinesterase, based on the pharmacophoric properties of Calyxamines A and B and their link to the active site of Acetylcholinesterase, using the innovative technique “Computational Nanotechnologyâ€.
To achieve this, we used a top of the line computational programs that currently support worldwide research in drug design as Sybyl®, Autodock, Gaussian®, VMD, Chimera UCFS® and others.
We elucidated the binding site of the Calyxamines A and B on the Acetylcholinesterase and the virtually complex they formed.
Thousands of compounds were designed “in silico†and their pharmacophoric activities fully evaluated on the active site of Acetylcholinesterase.
Then, through a rigorous chemical analysis of the interactions, was recognized a single lead drug candidate.
Finally, we found an organic compound that has a higher binding affinity to the Acetylcholinesterase than Calyxamines A and B, and knows exactly the binding site of these amines on the Acetylcholinesterase, using a method that has been called "intelligent drug design".
The impact of this research in the field of public health, is the contribution by our country in the design of potentially new drugs, aided by the new technique of “intelligent design drugs†that provides Computational Nanotechnology.
Furthermore, this contribution to science is expected to achieve an advance in the development and progress in the scientific research activities in Guatemala.
The use of Computational Nanotechnology in drug design is cheaper compared with current drug design methodology, which implies that Guatemala has the potential to design new drugs drugs to unravel in our region specific health problems.
In the development of active drugs against Alzheimer's Disease, this alternative has the advantage of design, constructed on the active site of the enzyme that wants to inhibit, on a directly way (and not by test and error as with the methods developed so far and that represents a cost of millions of dollars to get a leader candidate), potentially new candidates against the disease. This work is a contribution in a possible treatment of Alzheimer Disease, that currently reaches 17,000 people in Guatemala (Guatemalan Association against Alzheimer, 2007), and has an economic impact of global scale in the treatment of one of the most common diseases of the elderly (Alzheimer's Disease International, 2009).
References
Referencias
Asociación Guatemalteca contra el Alzheimer. (2007). Informe Anual.
Alzheimer's Association. (2009). Alzheimer's disease facts and figures. Alzheimer’s Dementia. 5(3), pp. 234-270.
Bagautdinov, B.; Yutani, K. (2008). Riken Structural Genomics-Proteomics, Initiative (Rsgi).
Cóbar, O.; Vásquez, A. (2005). Síntesis y Actividad Biológica de Calyxaminas y Calyxolanos, Dos Nuevas Clases de Productos Naturales Marinos. Resúmenes de Proyectos de Investigación, Dirección General de Investigación. Universidad de San Carlos de Guatemala, pp. 26-29.
Cachau, R.; Gonzalez-Nilo, F.; Ventura, N.; Fritts, N. (2007). In silico nanobio-design. A new frontier in computational biology. Current Topics in Medicinal Chemistry. 7(15), pp. 1537-40.
Gil-Néciga, E.; Gobartt, A. (2008). Treatment pattern of Alzheimer´s disease with cholinesterase inhibitors. Reviews of Neurology. 46(8), pp. 461-464.
Guo, J.; Hurley, M.; Wright J.; Lushington G. (2004). A docking score function for estimating ligand-protein interactions: application to acetylcholinesterase inhibition. Journal of Medicinal Chemistry. 22, pp. 5492-5000.
Harel, M.; Schalk, I.; Ehter-Sabatier, L.; Bouet, F.; Goeldner, M.; Hirth, C.; Axelsen, Ph.; Silman, I.; Sussamn, J. (1993). Quaternay ligand binding to aromatic residues in the active-site of acetylcholinesterase. Proccedings of the National Academy of Science, USA. 90, pp. 9031-9035.
Kubis, A.; Janusz, M. (2008). Alzheimer's disease: new prospects in therapy and applied experimental models. Posterapy High Medical Dosw (Online). Aug 5, 62, pp. 372-392.
Landmark, K.; Reikvam, A. (2008). Cholinesterase inhibitors in the treatment of dementia; are they useful in clinical practice? Tidsskr Nor Laegeforen. 128(3), pp. 294-297.
Lee, S.; Van H.; Yang, S.; Lee, K.; Kwon, Y.; Cho, W. (2009). Molecular design, synthesis and docking study of benz[b]oxepines and 12-oxobenzo[c]phenanthridinones as topoisomerase I inhibitors. Bioorganic and Medicinal Chemistry Letters. 19(9), pp. 2444-2447.
Lucas, S.; Heim, R.; Negri, M.; Antes, I.; Ries, C.; Schewe, K.; Bisi, A.; Gobbi, S.; Hartmann, R. (2008). Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach. Journal of Medicinal Chemistry. 51(19), pp. 6138-6149.
Massoulié, J.; Pezzementi, L.; Bon, S.; Krejci, E.; Vallette, F. (1993). Molecular and cellular biology of cholinesterases. Progress in Neurobiology. 41, pp. 31-91.
Pepeu, G.; Giovannini, M. (2009). Cholinesterase inhibitors and beyond. Current Alzheimer Research. 2, pp. 86-96.
Rodrıguez, A.; Cobar, O.; Padilla, O.; Barnes, C. (1997). Calyxamines A and B, Novel Piperidine Alkaloids from the Caribbean Sea Sponge Calyx podatypa. Journal of Natural Products, 60, pp. 1331-1333.
Shevtsov, P.; Shevtsova, E.; Burbaeva G. (2008). Effect of tacrine, amiridine, akatinol memantine, and triazolam on phosphorylation, structure, and assembly of microtubules from brain microtubular proteins in Alzheimer diseases. Bulletin of Experimental Biology Medicine. 145(2), pp. 218-222.
Song, C.; Lim, S.; Tong, J. (2009). Recent advances in computer-aided drug design. Advance Access, Oxford Journals, Brief Bioinform. 8 pp.
Taylor, P.; Radié, Z. (1994). The cholinesterases from genes to proteins. Annual Reviews in Pharmacology and Toxicology. 34, pp. 281-320.
Tiseo, P.; Perdomo, C.; Friedhoff, L. (1998). Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study. British Journal of Clinical Pharmacology. Suppl. 1, pp. 19-24.
