DUGi

Estudi computacional de la Estudi computacional de la flexibilitat de la proteïna FPPS i mecanisme d’inhibició al·lostèric

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The enzyme farnesyl pyrophosphate synthase (FPP) is a protein involved in the route of mevalonate present in tumour cells. Inhibiting this enzyme causes the apoptosis of carcinogenic. The most used drugs to inhibit this enzyme have been identified. Therefore it is interesting to design new drugs for this enzyle. For the computational design of new drugs using molecular docking techniques it is very important to have the structure of the pretein that one tries to inhibit. Because of it, this protein needs to be in the suitable conformation. To obtain this certain conformation, it is necessary to know the motions that take place intor the protein, the interactions and the behaviour of the active or allosteric site. To analyse these parameters in this study we have performed molecular dunamics simulations of FPPS to elucidate the dynamic changes that take place in its structure. We have carried out a simulation the apo (FPPS) and holo (FPPS + inhibitor) state. The obtained results show that FPPS is a higly flexible protein in the apo state and it can alternate between an open and closed conformation. From these two simulations the most relevant structures have been extracted and docking has been carried out with two different ligand. First, we hava performed the docking ot the GPP substrate into the selected conformations of the protein. Th GPP is a substrate of the FPPS that is placed in the active centre of the protein. using the docking results and visualization techniques, the position and the interaction energy of the substrate on the active site has been analysed, to know which is the most appropiate structure for the design of novel active site drugs. Secondly the docking was performed with the ligand BFH on the selected conformations. The BFH is an allosteric inhibitor of FPPS that does not contain the bisphosphonate group. By visualizing the results we were able to analyse the position that BFH adopts in the allosteric site and which are the most important amino acids to account for this interaction. Though the analysis of the orientation energy of the GPP and BFH ligands in the active/allosteric site respectively, we have been able to select the best conformations of the active and allosteric sites that can be used for the future design of drugs targeting the FPPS protein