Diseño in silico de inhibidores alostéricos de proteínas de unión a nucleótidos
- Autores: Patricia Gómez Gutiérrez
- Directores de la Tesis: Juan Jesús Pérez González (dir. tes.)
- Lectura: En la Universitat Politècnica de Catalunya (UPC) ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Angel Messeguer Peypoch (presid.), Hugo Omar Villar (secret.), Jaime Rubio Martínez (voc.)
- Programa de doctorado: Programa de Doctorado en Polímeros y Biopolímeros por la Universidad Politécnica de Catalunya
- Materias:
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- Resumen
One of the most important problems that the development of new bioactive compounds faces is the lack of selectivity towards a biological target of pharmacological interest. The ability of a compound to recognize other cellular receptors, in addition to the therapeutic target, can lead to toxicity problems that invalidate drug design programs at advanced stages of development. Selectivity problems are particularly significant in very large protein families and with highly conserved active sites that bind the same endogenous ligand. In these cases, the traditional therapeutic strategy of inhibition of the active, or orthosteric site, may not be suitable due to the complexity of designing compounds that bind with an adequate selectivity profile. On the other hand, allosteric inhibitors tend to be more selective. Allosteric inhibitors are those that bind to sites on proteins that are topographically distinct from the orthosteric site, called allosteric sites. Usually allosteric sites are less conserved regarding structure and sequence than the active sites, since the latter have been subjected to a big evolutionary pressure in order to preserve their function.
Proteins that bind nucleotides in their active site belong to very large protein families. Specifically, the family of protein kinases, to which p38a belongs, contains approximately 500 members and the ATP binding site is highly conserved among all of them. On the other hand, K-Ras is a protein of the group of GTPases that comprises more than 100 members that bind GTP on a very conserved active site. Furthermore, in this case, the high affinity of the GTP makes the design of selective inhibitors of the active site unfeasible. Due to these difficulties there are currently no drugs on the market targeting these two proteins. P38a is a protein kinase involved in pro-inflammatory cytokines production and it is considered a good therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, psoriasis, chronic asthma, Alzheimer's disease and chronic obstructive pulmonary disease. On the other side, proteins of the Ras family, including KRas, appear mutated in approximately 30% of human cancers. In particular, in cancers that are often resistant to the available treatments, such as some types of pancreatic, lung and colon cancers.
In the present doctoral thesis, the identification of potential allosteric sites and the design of new allosteric inhibitors of p38 a and K-Ras proteins by means of computational methods have been addressed. Accelerated molecular dynamics was used to carry out a study of the dynamics of both proteins. This study has allowed to select a set of representative conformations on which potential allosteric sites have been identified by molecular docking. In addition, inhibitors of the two proteins have been discovered through virtual screening of databases of low molecular weight commercial compounds.
