Abstract: The aggregation of the amyloid-β-peptide (AβP) into well-ordered fibrils has been considered as the key pathological marker of Alzheimer’s disease. Molecular attributes related to the specific binding interactions, covalently and non-covalently, of a library of compounds targeting of conformational scaffolds were computed employing static lattice atomistic simulations and array constructions. A combinatorial approach using isobolographic analysis was stochastically modeled employing Artificial Neural Networks and a Design of Experiments approach, namely an orthogonal Face-Centered Central Composite Design for small molecules, such as curcumin and glycosylated nornicotine exhibiting concentration-dependent behavior on modulating AβP aggregation and oligomerization. This work provides a mathematical and in silico approach that constitutes a new frontier in providing neuroscientists with a template for in vitro and in vivo experimentation. In future this could potentially allow neuroscientists to adopt this in silico approach for the development of novel therapeutic interventions in the neuroprotection and neurotherapy of Alzheimer’s disease. In addition, the neuroprotective entities identified in this study may also be valuable in this regard.
Keywords: amyloid-β protein; Alzheimer’s disease; molecular mechanics; artificial neural networks; curcumin; nicotine; isobolographic analysis; docking; central composite design; constraint optimization; ligand-protein complexes; synergism
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Kumar, P.; Pillay, V.; Choonara, Y.E.; Modi, G.; Naidoo, D.; Du Toit, L.C. In Silico Theoretical Molecular Modeling for Alzheimer’s Disease: The Nicotine-Curcumin Paradigm in Neuroprotection and Neurotherapy. Int. J. Mol. Sci. 2011, 12, 694-724.
Kumar P, Pillay V, Choonara YE, Modi G, Naidoo D, Du Toit LC. In Silico Theoretical Molecular Modeling for Alzheimer’s Disease: The Nicotine-Curcumin Paradigm in Neuroprotection and Neurotherapy. International Journal of Molecular Sciences. 2011; 12(1):694-724.
Kumar, Pradeep; Pillay, Viness; Choonara, Yahya E.; Modi, Girish; Naidoo, Dinesh; Du Toit, Lisa C. 2011. "In Silico Theoretical Molecular Modeling for Alzheimer’s Disease: The Nicotine-Curcumin Paradigm in Neuroprotection and Neurotherapy." Int. J. Mol. Sci. 12, no. 1: 694-724.