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Computational Studies of Macrocycles and Molecular Modeling of Hepatitis C Virus NS3 Protease Inhibitors
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. , s. 72
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 247
Nyckelord [en]
Drug discovery, HCV NS3 protease, macrocycles, conformational analysis, docking.
Nationell ämneskategori
Läkemedelskemi
Forskningsämne
Läkemedelskemi
Identifikatorer
URN: urn:nbn:se:uu:diva-340865ISBN: 978-91-513-0234-8 (tryckt)OAI: oai:DiVA.org:uu-340865DiVA, id: diva2:1180102
Disputation
2018-03-23, B21, BMC, Husargatan 3, Uppsala, 09:15 (Svenska)
Opponent
Handledare
Tillgänglig från: 2018-03-02 Skapad: 2018-02-04 Senast uppdaterad: 2018-04-03
Delarbeten
1. Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
Öppna denna publikation i ny flik eller fönster >>Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
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2018 (Engelska)Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 148, s. 453-464Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R-3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on beta-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the beta-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype la, both wild-type (K-i=30 nM) and R155K (K-i=2 nM), and genotype 3a (K-i=5 nM).

Ort, förlag, år, upplaga, sidor
Elsevier, 2018
Nyckelord
Hepatitis C, NS3, Genotype 3, Resistance, Pyrazinone
Nationell ämneskategori
Läkemedelskemi
Forskningsämne
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-340862 (URN)10.1016/j.ejmech.2018.02.032 (DOI)000428824700036 ()
Forskningsfinansiär
Vetenskapsrådet, D0571301
Tillgänglig från: 2018-02-04 Skapad: 2018-02-04 Senast uppdaterad: 2018-05-31Bibliografiskt granskad
2. A study of conformational energy penalties of protein-bound macrocycles
Öppna denna publikation i ny flik eller fönster >>A study of conformational energy penalties of protein-bound macrocycles
(Engelska)Ingår i: Artikel i tidskrift (Refereegranskat) Submitted
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-340863 (URN)
Tillgänglig från: 2018-02-04 Skapad: 2018-02-04 Senast uppdaterad: 2018-02-04
3. Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
Öppna denna publikation i ny flik eller fönster >>Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-340864 (URN)
Tillgänglig från: 2018-02-04 Skapad: 2018-02-04 Senast uppdaterad: 2018-02-04
4. Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
Öppna denna publikation i ny flik eller fönster >>Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
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2017 (Engelska)Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, nr 2, s. 190-202Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-318050 (URN)10.1021/acs.jcim.6b00443 (DOI)000395226100010 ()28079375 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 521-2014-6711
Tillgänglig från: 2017-03-23 Skapad: 2017-03-23 Senast uppdaterad: 2018-03-05Bibliografiskt granskad
5. Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
Öppna denna publikation i ny flik eller fönster >>Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
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2014 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 22, nr 23, s. 6595-6615Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.

Nyckelord
HCV, NS3, Protease inhibitors, Macrocyclization, Phenylglycine, Metathesis
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-239738 (URN)10.1016/j.bmc.2014.10.010 (DOI)000345287300007 ()
Tillgänglig från: 2014-12-31 Skapad: 2014-12-30 Senast uppdaterad: 2018-02-04Bibliografiskt granskad
6. Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
Öppna denna publikation i ny flik eller fönster >>Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
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2014 (Engelska)Ingår i: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, nr 3, s. 249-254Artikel i tidskrift, Letter (Refereegranskat) Published
Abstract [en]

Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-221229 (URN)10.1021/ml400217r (DOI)000333006200005 ()
Tillgänglig från: 2014-03-26 Skapad: 2014-03-26 Senast uppdaterad: 2018-02-04Bibliografiskt granskad

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