In accordance with the structure of Scientific Revolutions, the Pharmaceutical Industry ran into non-innovative, “deadendstreet” eras, several times during its modern history. Such intellectually infertile periods were followed eachtime by thought Renaissances, due to the application of new modes of thinking and novel philosophies, amountingto nothing less than characteristic Paradigm-shifts. Acceptance of the shift in thought coupled with the applicationof associated novel technologies, resulted each time in a corresponding Breakthrough; one may assign the followingapproximate years to these: 1920s, 1950s, 1980s (within ±5 years), breakthroughs occurring in 30 year intervals.We are now approaching a new Breakthrough, perhaps in 2010 or soon thereafter. Those who marshal in the newtechnology will take advantage of the emerging new Molecular Revolution. In essence, their advanced knowledgewill allow them to apply the new technology before anybody else does, allowing them to become leaders of a multitrillion-dollar Pharmaceutical Industry.
[Show abstract][Hide abstract] ABSTRACT: CDK2 of these proteins regulate the cell cycle of various cells. This study is about cyclin-dependent kinases (CDKs) using two different approaches. In the first part of the analysis was the comparison of sequences of active sites several types of CDKs. It analyzed the aminoacids in conserved positions in active sites of CDKs and contacts with ligands at crystallographic structures of these proteins, they are obtained from the database of the PDB. The results show that despite the great diversity of sequences of proteins analyzed, there is a great conservation of aminoacid sites and those aminoacids incontact with crystallographic ligands. The analysis showed that greater diversity between the structures was considered that the aminoacids present in at least 50% of active sites analyzed. The types of contact conducted between CDKs and the ligand analyzed using the NSC, were not and able to differentiate the various CDKs. As well, the comparison of maps pharmacophore, generated by the THINK and analyzed by 3DPharma, was not able to differentiate and CDKs. These results show that although there is some diversity in the aminoacids in the active sites and which have contact with the ligands, the ability to make interactions with the ligands is highly conserved. This is probably due to the common origin of kinases, which have the same function as phosphorylation of other proteins and a highly conserved active site for binding of ATP. In the second part was used virtual screening techniques for selecting CDK2 ligands. To get information about active ligands for these protein, i was used databases: DrugBank, PDB and the Wombat. DUD (Directory of Useful Decoys) was used to obtain series of ligands active and for inactive CDK2. The structures of these molecules were compared based on 2D similarities, for chemical and pharmacophore fingerprint, and 3D similarities, by pharmacophore fingerprint. 2D Similarity produced better results than 3D similarity as showed in the enrichment curves produced. The results obtained by comparing 3D is compatible with results published recently for the same series of compounds.
12/2009, Degree: Academic Specialization in Bioinformatics, Supervisor: Julio Cesar Dias Lopes
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