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Diseño Por Topología Molecular Y Ensayos Farmacológicos De Nuevos Antiinflamatorios

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Diseño Por Topología Molecular Y Ensayos Farmacológicos De Nuevos Antiinflamatorios UNIVERSITAT DE VALENCIA !"#$"%&'"()*(+,"-)',#,*&(.(/&%-&#,&( ! !"#$%&'(&)'*&(&+&,-.'/&+$01+.)'2'$3#.2&#'4.)/.0&+5,"0&#' !$'31$6&#'.3*""34+./.*&)"&#' !,%)#$"%)01( <)0,0(!"#$"%&7( 2&%,(3&%-)*(4)#,"(567)0,&0( 2&%:&(9=7>)?(@7"-A&%$( 4&-8*(9&%#:&(!"-)*)#;( B&7)*#,&C(DEFG( ! ! ! ! ! ! ! ! "!#$!%$&'! "!#$!#'($)*! "!#$!+'#$,$'! ! ! ! !"#!$%&'('%)*+,- A mi directora, Mari Carmen, por su cercanía, su amabilidad y por haberme transmitido la pasión por la Farmacología. A mi codirector, Ramón, por su paciencia, su afabilidad y por haber sabido guiarme en todas las etapas de mi carrera investigadora sin dejar de creer en mí. A la Universitat de Valencia, por los medios puestos a mi disposición y permitirme disfrutar del programa de Atracció de Talents durante 4 maravillosos años. A la Università di Bologna, por la gran acogida que siempre me ha brindado. Concretamente, a la Prof. Patrizia Romualdi, la coordinadora erasmus que cambió mi vida. Gracias a ti conocí al que es hoy mi marido y gracias a ti conocí lo que significa trabajar por primera vez en un laboratorio extranjero. Gracias a todas las personas con las que compartí mi estancia en Italia. Gracias al Dr. Alberto del Rio, por su disponibilidad, su comprensión y su paciencia, me enseñaste que se puede emprender y ser científico al mismo tiempo. A todos los compañeros/as y profesores visitantes que he podido conocer a lo largo de estos años en el laboratorio de Farmacología. A todos los del departamento de Farmacología y del de Química Física que he tenido el gusto de conocer: Rosa, José Luís, Salva, Mamen, Lionello, Olga, Facundo, Julián, Juan Luis, Nacho, Pepe… A mi padre, Jorge, por haberme transmitido la pasión por la Topología molecular. He hecho mía tu lucha porque esta disciplina de la química matemática se reconozca algún día como el paradigma nuevo que representa. Dicen que tenemos el mismo carácter (yo espero que no sea así), pero algo de razón tienen que llevar porque somos igual de testarudos. A mi madre, María José, por ser la mujer que más admiro la que desde pequeña me transmitió la cultura del esfuerzo y del trabajo diario. Gracias a ti he logrado llegar a este momento. Gracias por ser amiga, compañera y, sobre todo, madre. Tú me has enseñado que hay que ser humilde y buena persona por encima de todo. Ahora que soy madre me doy cuenta de que la ciencia es apasionante, pero formar parte de una familia es lo más importante para mí. En eso tú has sido mi “directora”. A mi marido, Riccardo, el amor de mi vida y la persona que tiene la paciencia de soportarme día tras día. Nos conocimos allá por septiembre de 2006 y quien nos iba a decir a nosotros que un Erasmus cambiaría tanto nuestras vidas. Allá por mayo de 2007 comenzamos a escribir juntos nuestra historia. Hoy te has convertido no solo en mi mejor amigo, mi marido y el padre de la luz de mi vida, sino que haces que cada día aprenda de ti y me vaya haciendo una mejor persona. Me transmites tu pasión por los pequeños detalles, tu cercanía con las personas, tu alegría y tu sentimiento de la justicia. Ti amo. A mi hija, Claudia, mi luz desde que llegaste a este mundo un 21 de febrero de 2014 y la lente con la cambié mi visión del mundo. Gracias porque cuando vuelvo del trabajo y he tenido un día duro y te veo de lejos se me dibuja una sonrisa que nadie puede borrar. Te amo. Al resto de mi familia, mi hermano Jorge, mi tía Helen, por compartir mis vivencias durante estos años. A mis amigos, vosotros sabéis quienes sois. Por estar siempre a mi lado y transmitirme vuestra pasión por vuestras profesiones, por apoyarme y escucharme tantas y tantas veces sobre lo duro que es la vida del investigador. Alla mia famiglia italiana, perche sempre ci aiutate dove e come sia per soppraporci ad ogni imprevisto. Perche mi avete fatto amare l’ Italia, la gente, il cibo e la cultura. A todas las personas que veo a diario y que me han hecho tan agradables estos años en la Universidad como el servicio de limpieza y el personal del bar de Farmacia. A todos a los que no he citado y habéis contribuido a que hoy esté escribiendo estas líneas. Por último, a todos los que ya no están y me hubiera gustado compartir con ellos este momento. Concretamente a ti, Marga. !! La presente Tesis Doctoral ha sido financiada por el proyecto SAF2009-13059-C03-02 concedido por el Ministerio Español de Ciencia e Innovación (MICINN) junto al fondo europeo de Desarrollo Regional y la ayuda concedida por la Universitat de València (UV-INV-AE14-265774). La realización de la presente Tesis Doctoral ha sido posible gracias al contrato predoctoral VLC-Campus d’ Atracció de talents, concedida por la Universitat de València. ! ! La presente Tesis Doctoral ha dado lugar a las siguientes publicaciones: ARTÍCULOS M. Gálvez-Llompart; R. M. Giner; M. C. Recio; S. Candeletti; R. García-Domenech. Application of Molecular Topology to the Search of Novel NSAIDs: Experimental Validation of Activity. Letters in Drug Design & Discovery, 2010, 7, 438-445. M. Gálvez-Llompart; M. C. Recio; R. García-Domenech. Topological virtual screening: a way to find new compounds active in ulcerative colitis by inhibiting NF-κB. Molecular Diversity, 2011, 15, 917–926. J. Galvez; M. Galvez-Llompart; R. García-Domenech. Molecular topology as a novel approach for drug discovery. Expert Opinion On Drug Discovery, 2012, 7(2), 133-153. J. Gálvez; M. Gálvez-Llompart; R. García-Domenech. Introduction to Molecular Topology: Basic Concepts and Application to Drug Design. Current Computer-Aided Drug Design, 2012, 8(3), 196- 223. M. Galvez-Llompart; M. C. Recio Iglesias; J. Gálvez; R. García-Domenech. Novel potential agents for ulcerative colitis by molecular topology: suppression of IL-6 production in Caco-2 and RAW264.7 cell lines. Molecular Diversity, 2013, 17(3),573– 593. R. García-Domenech; M. Gálvez-Llompart; R. Zanni; M. C. Recio; J. Gálvez. QSAR methods for the discovery of new inflammatory bowel disease drugs. Expert Opinion On Drug Discovery, 2013, 8(8), 933- 949. R. Zanni; M. Galvez-Llompart; R. García-Domenech; J. Galvez. Latest advances in molecular topology applications for drug discovery. Expert Opinion On Drug Discovery, 2015, 10(9), 945-957. !"# $%&'()*+&,-./012# !"# 3"# 4(56,2# 4"# $/057/*8,-(9(5:2# ;"# $%&'()"# !,&(5<&/0# 1,.,&,=>?#@#A10/1(=>#1,#6B(916C>#9,'(&#5,-.,<9BA#/=/69A1#<&5(0/16'(#5,&616A!"!"#$%&#'() *+,$(-+./)#$%&0)1112))34,+'5"2 COMUNICACIONES A CONGRESOS J. Gálvez Alvarez; M. Gálvez Llompart; R. García Domenech. Application of Molecular Topology to the Search of New Compounds Active in Ulcerative Colitis and Crohn’s Disease. 11th Annual Drug Discovery, Montreux (Suiza), 2010. COMUNICACIÓN ORAL. M. Galvez-Llompart; R. Zanni; R. Garcia-Domenech. New inhibitors of IL-6 production in Caco-2 cells through molecular topology methodology. XXXIII Congreso Nacional de la Sociedad Española de Farmacología, Malaga (España), 2011. POSTER. M. Galvez-Llompart; M. C. Recio; R. Garcia-Domenech. New compounds against ulcerative colitis through molecular topology. European Crohn’s and Colitis Organisation Congress, Barcelona (España), 2012. POSTER. ÍNDICE I. RESUMEN ............................................................................................................................... 3 II. INTRODUCCIÓN ................................................................................................................. 9 II.1. DISEÑO Y DESCUBRIMIENTO DE FÁRMACOS ASISTIDO POR ORDENADOR . 9 II.2. QSAR .............................................................................................................................. 13 II.3. TOPOLOGÍA MOLECULAR ........................................................................................ 17 II.3.1. Teoría de Grafos ..................................................................................................... 17 II.3.1.1. Principios ........................................................................................................... 17 II.3.1.2. Moléculas representadas como grafos ............................................................... 21 II.3.2. Índices topológicos ................................................................................................. 22 II.3.3. Diseño de fármacos por Topología molecular ..................................................... 28 II.4. INFLAMACIÓN ............................................................................................................. 31 II.4.1. Enfermedades inflamatorias ................................................................................. 32 II.4.2. Principales mediadores inflamatorios .................................................................. 34 II.5. ENFERMEDAD INFLAMATORIA INTESTINAL ...................................................... 36 II.5.1. Colitis ulcerosa ....................................................................................................... 36 II.5.1.1. Factores implicados en la CU ............................................................................ 37 II.5.1.2. Prevalencia e incidencia de la CU ..................................................................... 39 II.5.1.3. Impacto socio-económico de la CU ................................................................... 39 II.5.1.4. Terapia actual de la CU ..................................................................................... 41 II.5.1.5. Mediadores implicados en la CU ....................................................................... 44 III. OBJETIVOS ......................................................................................................................
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