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| About Alessandro Contini (University of Milan) |
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Alessandro Contini graduated with a degree in Chemistry and Pharmaceutical Technologies from the University of Milan in 1999. After a period of service in the army as medical assistant, he started a Ph.D. program in medicinal chemistry as a synthetic organic chemist. However he soon recognized that organic synthesis was not the best way to spend his life and, encouraged by his mentor Prof. P. Trimarco, shifted his interests towards computational chemistry. After a short period at the ETH, Zurich, where he learned the basis of molecular modeling, he obtained his Ph.D. from the University of Milan in 2003. He continued as a post-doc fellow at the Institute of Organic Chemistry at the Faculty of Pharmacy, University of Milan, studying organic reaction mechanisms [1] and predicting optical and spectroscopic properties of organic molecules [2] by using quantum-mechanical techniques. However, when he realized that those fields, even if valuable for increasing humanity's knowledge, didn't attract any of the already scarce funds available in Italy, he redirected his research efforts in the more remunerative field of drug discovery [3]. Dr. Contini holds a permanent position as Assistant Professor of Organic Chemistry and teaches organic chemistry in the degree of Biotechnology. His research interests are mainly oriented towards computer-aided discovery and/or design of bioactive molecules [4], but in his spare time he still loves challenging his mind with “funding-unattractive” reaction mechanisms [5].
References
[1] [2+4] and [4+2] Cycloadditions of o-Thioquinones with 1,3-dienes: a Computational Study A. Contini, S. Leone, S. Menichetti, C. Viglianisi, P. Trimarco J. Org. Chem. 2006, 71, 5507-5514.
[2] Tautomeric Equilibria of [1]Benzopyrano[3,4-d]imidazol-4(3H)-ones, a Theoretical and NMR Study A. Contini, D. Nava, P. Trimarco J. Org. Chem. 2006, 71, 159-166.
[3] SAR and QSAR Study on 2-Aminothiazole Derivatives, Modulators of Transcriptional Repression in Huntington's Disease” S. Leone, C. Mutti, A. Katzantsev, E. Cattaneo, M. Sturlese, S. Moro, D. Rigamonti, A. Contini Bioorg. & Med. Chem. 2008, 16, 5695-5703
[4] Virtual screening approach for the identification of new Rac1 inhibitors N. Ferri, A. Corsini, P. Bottino, F. Clerici, A. Contini J. Med. Chem. 2009, 52, 4087-4090.
[5] Addition of Sulfenic Acids to Monosubstituted Acetylenes: a Theoretical and Experimental Study M. C. Aversa, A. Barattucci, P. Bonaccorsi, A. Contini J. Phys. Org. Chem. 2009, 22, 1048-1057
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Consensus Strategies for Challenging Dockings
Alessandro Contini (University of Milan)
The attention toward protein-protein interactions as potential targets for the design of very specific drugs dramatically increased during the last few years. The binding regions involved in protein-protein interactions are rarely deep and well-defined cavities, as found in the active site of an enzyme, but are often characterized by solvent-exposed clefts on the protein surface. This feature makes the definition of a reliable docking protocol quite challenging.
This workshop will be focused upon the development of a docking protocol for the identification of small organic molecules potentially able to interfere with the interaction of two target proteins (hereafter referred as proteins A and B). The study will cover two possible scenarios:
1) The crystal structure of the AB complex is available;
2) The structure of either A or B is available co-crystallized with a known inhibitor.
In both scenarios we will analyze the complex, finding and fixing all possible sources of error and preparing the model for docking experiments (fixing missing residues, assigning the correct protonation state, relaxing the structure through short molecular dynamic runs followed by geometry minimizations). A docking protocol will then be realized and tested through the docking of small databases of compounds with known activity. The results of both scenarios will be compared and discussed.
As consensus between different computational methods might be a key to improve the success rate of a virtual screening procedure, an alternative docking protocol will be also realized by using a different method and software. The two protocols will be tested within a virtual screening case study and those hits identified by each single protocol will be compared to those identified by both protocols applied on a consensus basis.
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