| 1. |
- Russo, Francesco, et al.
(författare)
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Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
- 2015
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Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 4:3, s. 342-362
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Tidskriftsartikel (refereegranskat)abstract
- This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.
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| 2. |
- Alogheli, Hiba
(författare)
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Computational Studies of Macrocycles and Molecular Modeling of Hepatitis C Virus NS3 Protease Inhibitors
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 3. |
- Alogheli, Hiba, et al.
(författare)
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Docking of Macrocycles : Comparing Rigid and Flexible Docking in Glide
- 2017
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 57:2, s. 190-202
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- De Rosa, Maria, et al.
(författare)
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Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB)
- 2017
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 25:3, s. 897-911
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Tidskriftsartikel (refereegranskat)abstract
- Type I signal peptidases are potential targets for the development of new antibacterial agents. Here we report finding potent inhibitors of E. coli type I signal peptidase (LepB), by optimizing a previously reported hit compound, decanoyl-PTANA-CHO, through modifications at the N- and C-termini. Good improvements of inhibitory potency were obtained, with IC50s in the low nanomolar range. The best inhibitors also showed good antimicrobial activity, with MICs in the low μg/mL range for several bacterial species. The selection of resistant mutants provided strong support for LepB as the target of these compounds. The cytotoxicity and hemolytic profiles of these compounds are not optimal but the finding that minor structural changes cause the large effects on these properties suggests that there is potential for optimization in future studies.
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| 5. |
- Eberhardson, Michael, et al.
(författare)
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Randomised, Double-blind, Placebo-controlled Trial of CCR9-targeted Leukapheresis Treatment of Ulcerative Colitis Patients.
- 2017
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Ingår i: Journal of Crohn's & colitis. - : Oxford University Press (OUP). - 1876-4479 .- 1873-9946. ; 11:5, s. 534-542
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Tidskriftsartikel (refereegranskat)abstract
- Ulcerative colitis patients display increased numbers of circulating pro-inflammatory monocyte human leukocyte antigen-DR [HLA-DRhi] monocytes expressing high levels of the gut-homing C-C chemokine receptor 9 [CCR9] and tumour necrosis factor [TNF]-α. The aim of this first-in-human, double-blind, randomised, placebo-controlled trial was to evaluate selective removal of circulating CCR9-expressing monocytes by leukapheresis in patients with moderate to severe ulcerative colitis, with regards to safety, tolerability, and immunological response.Patients with ulcerative colitis were treated every second day with leukapheresis during five sessions with a C-C chemokine ligand 25 [CCL25; CCR9 ligand] column or a placebo column.No major safety concerns were raised and the procedure was well tolerated. Pro-inflammatory HLA-DRhi cells decreased significantly in the active treatment group [p = 0.0391] whereas no statistically significant change was seen in the placebo group [p = 0.4688]. There was a significant decrease of HLA-DRhi monocytes in the active group compared with the placebo group when corrected for the imbalance in weight between the groups [p = 0.0105]. Mayo score decreased in the active group [p = 0.0156] whereas the change in the placebo group was not significant [p = 0.1250]. Mayo score ≤ 3 was observed in five out of 14 patients [35.7%] in the active group compared with one out of eight [12.5%] receiving placebo. The number of responders in the active treatment group was eight out of 14 patients [57.1%], whereas in the corresponding placebo group three out of eight patients [37.5%] responded to placebo. A dose-response correlation was observed between the blood volume processed and clinical outcome.This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis.
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| 6. |
- Hildebrand Karlén, Malin, 1984, et al.
(författare)
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Alcohol intoxicated eyewitnesses’ memory of intimate partner violence
- 2015
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Ingår i: Psychology, Crime and Law. - 1068-316X. ; 21:2, s. 156-171
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol affects memory in many, and mostly negative, ways. This is a problem in legal contexts as many witnesses are alcohol intoxicated when taking part of the critical event. However, research is sparse regarding how, and under what circumstances, the reports of alcohol intoxicated witnesses differ from those of sober witnesses. This study investigated if alcohol intoxicated and sober eyewitnesses differ regarding completeness, accuracy, and type of information reported, as well as if gender influenced these variables. Eighty-seven healthy men (n=44) and women (n=43) received either an alcoholic beverage (0.7g/kg) or a control (juice) in a laboratory setting before viewing a film picturing intimate partner violence. Ten minutes after viewing the film, they were interviewed. Reports by alcohol intoxicated women were less complete, but as accurate, as sober women’s. In contrast, intoxicated and sober men did not differ regarding completeness or accuracy. Furthermore, compared to sober women, intoxicated women reported fewer actions but no difference was found between the groups regarding reported objects. At this moderate dose, alcohol affected women’s reports more than men’s, which may be because alcohol affects attention and memory consolidation more clearly at a lower dose for women than for men.
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| 7. |
- Hildebrand Karlén, Malin, 1984, et al.
(författare)
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Alcohol Intoxicated Witnesses: Perception of Aggression and Guilt in Intimate Partner Violence
- 2017
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Ingår i: Journal of Interpersonal Violence. - : SAGE Publications. - 0886-2605 .- 1552-6518. ; 32:22, s. 3448-3474
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Tidskriftsartikel (refereegranskat)abstract
- Many witnesses to violent crimes are alcohol intoxicated, but research is lacking regarding how alcohol affects their perception of aggression and guilt. This study investigated to what extent alcohol intoxicated eyewitnesses differed from sober witnesses regarding how aggressive and guilty they perceived the involved parts in an intimate partner violence (IPV) situation. Eighty-seven healthy men (n = 44) and women (n = 43) were randomized to an alcohol group (0.7 g/kg) or a non-alcohol group. In a laboratory setting, alcoholic/non-alcoholic drinks were consumed before viewing a film depicting IPV between a man and a woman. Ten min after viewing, in an interview, the participants rated how aggressive and guilty they perceived the involved parts to be. Alcohol intoxicated participants perceived both parts’ physically aggressive behavior as comparatively less severe, but their neutral behavior as more hostile. Sober witnesses perceived the man to be the most guilty part, whereas intoxicated witnesses distributed guilt more evenly. Alcohol had a strong but complex impact on the perception of aggression in IPV (i.e., heightened during the neutral interaction and lowered during physical aggression). These results may be explained by the cognitive consequences of alcohol’s anxiety-dampening effects. Regarding the asymmetric difference in perceived guilt, stereotypical expectations of gender-appropriate behavior in an IPV situation may need to be considered.
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| 8. |
- Hildebrand Karlén, Malin, 1984, et al.
(författare)
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To wait or not to wait? Improving results when interviewing intoxicated witnesses to violence
- 2017
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Ingår i: Scandinavian Journal of Psychology. - : Wiley. - 0036-5564. ; 58:1, s. 15-22
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Tidskriftsartikel (refereegranskat)abstract
- Witnesses to violent crimes are often alcohol intoxicated, but few studies have investigated the impact of alcohol on witness reports. This study investigated how alcohol intoxication and time of interview affected reports of intimate partner violence (IPV). One hundred thirty six healthy men (N = 66) and women (N = 70) were randomized to an alcohol group (0.8g/kg for men, 0.75g/kg for women) (N = 70) or control group (N = 66), given juice. Participants consumed drinks in a laboratory setting before they witnessed an IPV scenario. Fifty percent of the intoxicated and sober participants were interviewed ten minutes after viewing the film and all participants were interviewed one week later. For the analyses, participants in the alcohol group were divided into two groups (moderately/highly intoxicated) based on their BAC-level. Ten minutes after viewing the event, highly (BAC = 0.08-0.15) intoxicated witnesses gave shorter, but as accurate, reports as moderately intoxicated/sober witnesses. All witnesses gave shorter and less accurate reports one week later compared to immediately after. However, an immediate interview increased completeness one week later. In general, time and high intoxication made witnesses give less detailed accounts of actions and verbal information, but not of objects. Highly intoxicated witnesses reported less actions and verbal information in all interviews, while information regarding objects was reported to a similar extent. At the present BAC-level, it is beneficial to conduct an immediate free recall interview with intoxicated witnesses to obtain a maximum amount of correct information and minimize the negative effect of time.
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| 9. |
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| 10. |
- Karlsson, Christoffer, et al.
(författare)
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Phototriggerable peptidomimetics for the inhibition of Mycobacterium turberculosis ribonucleotide reductase by targeting protein-protein binding
- 2015
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Ingår i: Organic and biomolecular chemistry. - 1477-0520 .- 1477-0539. ; 13:9, s. 2612-2621
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Tidskriftsartikel (refereegranskat)abstract
- Incorporation of an artificial amino acid 2 with a stilbene chromophore into peptidomimetics with three to nine amino acids yields phototriggerable candidates for inhibition of the binding between the R1 and R2 subunits of the M. tuberculosis ribonucleotide reductase (RNR). Interstrand hydrogen bond probability was used as a guideline for predicting conformational preferences of the photoisomers. Binding of these inhibitors has been rationalized by docking studies with the R1 unit. Significant differences in binding of the photoisomers were observed. For the shorter peptidomimetics, stronger binding of the Z isomer might indicate hydrophobic interactions between the stilbene chromophore and the binding site.
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