Computational Studies of Macrocycles and Molecular Modeling of Hepatitis C Virus NS3 Protease Inhibitors

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Fältnamn	Indikatorer	Metadata
000		05118nam a2200433 4500
001		oai:DiVA.org:uu-340865
003		SwePub
008		180204s2018 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
020		a 9789151302348q print
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3408652 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 Alogheli, Hibau Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 aut0 (Swepub:uu)hibhu475
245	1 0	a Computational Studies of Macrocycles and Molecular Modeling of Hepatitis C Virus NS3 Protease Inhibitors
264	1	a Uppsala :b Acta Universitatis Upsaliensis,c 2018
300		a 72 s.
338		a electronic2 rdacarrier
490	0	a Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy,x 1651-6192 ;v 247
520		a Computational tools are utilized in the drug discovery process to discover, design, and optimize new therapeutics. One important approach is structure-based drug design which relies on knowledge about the 3D structure of the biological target. The first part of this work focuses on applying structure-based drug design for binding mode prediction of HCV NS3 protease inhibitors. The NS3 protease is a challenging target from a computational perspective as it contains an extended binding site. Binding mode predictions were performed for various classes of new acyclic and macrocyclic HCV NS3 protease inhibitors and was used in the design of new inhibitors. None of the synthetized inhibitors have been co-crystallized yet, which has made the evaluation of the suggested binding mode predictions challenging.Macrocycles are an interesting compound class in drug discovery due to their unique structural architecture, which can enable access to new chemical space. Macrocycles can successfully modulate difficult therapeutic targets, as exemplified in the development of protease inhibitors. Furthermore they can improve drug-like properties, such as cell permeability and bioavailability. The second part of this thesis focuses on macrocycles from a computational point of view. A data set of 47 clinically relevant macrocycles was compiled and used in these studies. First, two different docking protocols rigid docking of pre-generated conformers and flexible docking in Glide were evaluated and compared. The results showed that flexible docking in Glide was sufficient for docking of macrocycles with respect to accuracy and speed.The aim of the second study was to evaluate and compare the performance of the more general conformational analysis tools, MCMM and MTLMOD, with the recently developed macrocycle-specialized conformational sampling tools, Prime-MCS and MMBS. In most cases, the general conformational analysis tools (with enhanced parameter settings) performed equally well as compared to the macrocycle-specialized conformational sampling techniques. However, MMBS was superior at locating the global energy minimum conformation.Finally, calculation of the conformational energy penalty of protein-bound macrocycles was performed. The macrocycle data set was complemented with linear analogues that are similar either with respect to physicochemical properties or 2D fingerprints. The conformational energy penalties of these linear analogues were calculated and compared to the conformational energy penalties of the macrocycles. The complete data set of macrocycles and non-macrocycles in this study differ from previously published work addressing conformational energy penalties, since it covers a more extended area of chemical space. Furthermore, there was a weak correlation between the calculated conformational energy penalties and the flexibility of the structures.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Läkemedelskemi0 (SwePub)301032 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medicinal Chemistry0 (SwePub)301032 hsv//eng
653		a Drug discovery
653		a HCV NS3 protease
653		a macrocycles
653		a conformational analysis
653		a docking.
653		a Medicinal Chemistry
653		a Läkemedelskemi
700	1	a Karlén, Anders,c Professoru Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 ths
700	1	a Sandström, Anja,c Associate professoru Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 ths
700	1	a Brandt, Peter,c Doctoru Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 ths
700	1	a Eriksson, Leif,c Professoru Department of Chemistry and Molecular Biology, University of Gothenburg4 opn
710	2	a Uppsala universitetb Avdelningen för organisk farmaceutisk kemi4 org
856	4	u https://uu.diva-portal.org/smash/get/diva2:1180102/FULLTEXT01.pdfx primaryx Raw objecty fulltext
856	4	u https://uu.diva-portal.org/smash/get/diva2:1180102/PREVIEW01.jpgx Previewy preview image
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-340865

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