Konformációs viszonyok és elektronszerkezet-változások vizsgálata fehérjékben = Investigation of conformational fluctuations and electronic structure variations in proteins

Felterkepeztuk a foszfoglicerat kinaz molekularis felismeresi folyamataiban szerepet jatszo konformacios valtozasokat. Elvegeztuk a foszfoinozitol kinaz 3 alfa izoformajannak 3D szerkezetpredikciojat, azonban a ligandumkotődes vizsgalatara a kooperalo partner elallasa miatt nem kerult sor. Felderitettuk a tetrahidribiopterin (BH4) kofaktor szerepe a nitrogen monoxid szintetaz (NOS) aktivalodasaban. Meghataroztuk a NO kotőhelyet a nitroforin 4 (NP4) feherje aktiv helyen. Low-mode (LMOD) keresesen alapulo platfromfuggetlen konformerkereső es dokkolo eljarast dolgoztunk ki, amely az AMBER programcsomagban is hozzaferhető. Elvegeztuk a kifejlesztett eljaras tobb konformerkereső modszerrel tortenő osszehasonlito vizsgalatat. Eljarast dolgoztunk ki human P450 2C9 ligandumok azonositasara es az izoforma specificitas vizsgalatara a 2C csaladban. Felderitettuk a NADH kofaktor es NO kolcsonhatas szerepet a P450 NO-reduktaz feherjeben. A tamogatott időszak alatt megkezdett hisztamin receptorok kutatasat erintő vizsgalataink alapjan uj lipofil zsebet talaltunk a H1 receptorban, ligandum informaciokkal segitett homologiamodellezessel előallitottuk a H4 receptor első atomi felbontasu modelljet es eljarast dolgoztunk ki uj H4 ligandunok azonositasara. Utobbi eljarast az eddig ismert legkiterjedtebb szerkezet alapu szűrővizsgalatban alkalmazva uj, kiserletileg is megerősitett H4 ligandumokat azonositottunk. | Conformational motions responsible for the substrate recognition in phosphoglycerate kinase have been explored. Homology model for phosphoinositol 3 kinase alpha isoform has been developed, however docking studies were suspended due to the changed interest of the partner (ComGenex Inc). The role of tetrahydrobiopterin cofactor in nitric oxide synthase has been clarified. The putative nitric oxide binding site in nitrophorin 4 has been identified. A platform-independent LMOD conformational search method has been developed and integrated to AMBER package at UCSF. The performance of this method has been evaluated and compared to other algorithms. A new virtual screening protocol has been developed for the identification of CYP 2C9 ligands. The protocol was useful for isofom specificity studies in the 2C family. The role of NADH-nitric oxide interaction in P450-No reductase has been investigated. A new lipophilic binding pocket in human histamine H1 receptor has been identified. The first atom-level model of human histamine H4 receptor has been constructed by ligand supported homology modelling. that was used to develop an effective virtual screening protocol. The protocol allowed us to perform the largest structure based virtual screening experiment using a screening database of more than 8 million compounds. Identified new chemical scaffolds showed submicromolar binding affinity towards the human histamine H4 receptor as revealed by experimental studies.