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| Fältnamn | Indikatorer | Metadata |
|---|---|---|
| 000 | 04766nam a2200541 4500 | |
| 001 | oai:DiVA.org:uu-230777 | |
| 003 | SwePub | |
| 008 | 140829s2014 | |||||||||||000 ||eng| | |
| 020 | a 9789155490201q print | |
| 024 | 7 | a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2307772 URI |
| 040 | a (SwePub)uu | |
| 041 | a engb eng | |
| 042 | 9 SwePub | |
| 072 | 7 | a vet2 swepub-contenttype |
| 072 | 7 | a dok2 swepub-publicationtype |
| 100 | 1 | a Keränen, Henrik,d 1983-u Uppsala universitet,Beräknings- och systembiologi,Johan Åqvist4 aut0 (Swepub:uu)henke383 |
| 245 | 1 0 | a Advances in Ligand Binding Predictions using Molecular Dynamics Simulations |
| 264 | 1 | a Uppsala :b Uppsala universitet,c 2014 |
| 300 | a 51 s. | |
| 338 | a electronic2 rdacarrier | |
| 490 | 0 | a Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology,x 1651-6214 ;v 1172 |
| 520 | a Biochemical processes all involve associations and dissociations of chemical entities. Understanding these is of substantial importance for many modern pharmaceutical applications. In this thesis, longstanding problems with regard to ligand binding are treated with computational methods, applied to proteins of key pharmaceutical importance. Homology modeling, docking, molecular dynamics simulations and free-energy calculations are used here for quantitative characterization of ligand binding to proteins. By combining computational tools, valuable contributions have been made for pharmaceutically relevant areas: a neglected tropical disease, an ion channel anti-drug-target, and GPCR drug-targets.We report three compounds inhibiting cruzain, the main cysteine protease of the protozoa causing Chagas’ disease. The compounds were found through an extensive virtual screening study and validated with experimental enzymatic assays. The compounds inhibit the enzyme in the μM-range and are therefore valuable in further lead optimization studies.A high-resolution crystal structure of the BRICHOS domain is reported, together with molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry studies. This work revealed a plausible mechanism for how the chaperone activity of the domain may operate.Rationalization of structure-activity relationships for a set of analogous blockers of the hERG potassium channel is given. A homology model of the ion channel was used for docking compounds and molecular dynamics simulations together with the linear interaction energy method employed for calculating the binding free-energies.The three-dimensional coordinates of two GPCRs, 5HT1B and 5HT2B, were derived from homology modeling and evaluated in the GPCR Dock 2013 assessment. Our models were in good correlation with the experimental structures and all of them placed among the top quarter of all models assessed. Finally, a computational method, based on molecular dynamics free-energy calculations, for performing alanine scanning was validated with the A2A adenosine receptor bound to either agonist or antagonist. The calculated binding free-energies were found to be in good agreement with experimental data and the method was subsequently extended to non-alanine mutations. With extensive experimental mutation data, this scheme is a valuable tool for quantitative understanding of ligand binding and can ultimately be used for structure-based drug design. | |
| 650 | 7 | a NATURVETENSKAPx Kemix Teoretisk kemi0 (SwePub)104072 hsv//swe |
| 650 | 7 | a NATURAL SCIENCESx Chemical Sciencesx Theoretical Chemistry0 (SwePub)104072 hsv//eng |
| 650 | 7 | a NATURVETENSKAPx Biologi0 (SwePub)1062 hsv//swe |
| 650 | 7 | a NATURAL SCIENCESx Biological Sciences0 (SwePub)1062 hsv//eng |
| 653 | a free-energy perturbation | |
| 653 | a molecular dynamics | |
| 653 | a ligand binding | |
| 653 | a free-energy perturbation | |
| 653 | a linear interaction energy | |
| 653 | a binding free-energy | |
| 653 | a homology modeling | |
| 653 | a virtual screening | |
| 653 | a alanine scanning | |
| 653 | a amino acid mutagenesis | |
| 653 | a hERG | |
| 653 | a GPCR | |
| 653 | a adenosine receptor | |
| 653 | a serotonin receptor | |
| 653 | a BRICHOS | |
| 653 | a cruzain | |
| 700 | 1 | a Åqvist, Johan,c Professoru Uppsala universitet,Beräknings- och systembiologi4 ths |
| 700 | 1 | a Villà i Freixa, Jordi,c Prof.u University of Vic4 opn |
| 710 | 2 | a Uppsala universitetb Beräknings- och systembiologi4 org |
| 856 | 4 | u https://uu.diva-portal.org/smash/get/diva2:741767/FULLTEXT01.pdfx primaryx Raw objecty fulltext |
| 856 | 4 | u https://uu.diva-portal.org/smash/get/diva2:741767/PREVIEW01.jpgx Previewy preview image |
| 856 | 4 8 | u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-230777 |
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