| 1. |
- Ericsson, Daniel J., et al.
(författare)
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Identification of small peptides mimicking the R2 C-terminus of Mycobacterium tuberculosis ribonucleotide reductase
- 2010
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 16:3, s. 159-164
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Tidskriftsartikel (refereegranskat)abstract
- Ribonucleotide reductase (RNR) is a viable target for new drugs against the causative agent of tuberculosis, Mycobacterium tuberculosis. Previous work has shown that an N-acetylated heptapeptide based on the C-terminal sequence of the smaller RNR subunit can disrupt the formation of the holoenzyme sufficiently to inhibit its function. Here the synthesis and binding affinity, evaluated by competitive fluorescence polarization, of several truncated and N-protected peptides are described. The protected single-amino acid Fmoc-Trp shows binding affinity comparable to the N-acetylated heptapeptide, making it an attractive candidate for further development of non-peptidic RNR inhibitors.
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| 2. |
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| 3. |
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| 4. |
- Nurbo, Johanna, et al.
(författare)
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Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
- 2007
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 13:12, s. 822-832
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Tidskriftsartikel (refereegranskat)abstract
- Mycobacterium tuberculosis ribonucleotide reductase (RNR) is a potential target for new antitubercular drugs. Herein we describe the synthesis and evaluation of peptide inhibitors of RNR derived from the C-terminus of the small subunit of M. tuberculosis RNR. An N-terminal truncation, an alanine scan and a novel statistical molecular design (SMD) approach based on the heptapeptide Ac-Glu-Asp-Asp-Asp-Trp-Asp-Phe-OH were applied in this study. The alanine scan showed that TrP5 and Phe7 were important for inhibitory potency. A quantitative structure relationship (QSAR) model was developed based on the synthesized peptides which showed that a negative charge in positions 2, 3, and 6 is beneficial for inhibitory potency. Finally, in position 5 the model coefficients indicate that there is room for a larger side chain., as compared to Trp5.
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| 5. |
- Nurbo, Johanna, et al.
(författare)
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Novel pseudopeptides incorporating a benzodiazepine-based turn mimetic – targeting Mycobacterium tuberculosis ribonucleotide reductase
- 2013
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 21:7, s. 1992-2000
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Tidskriftsartikel (refereegranskat)abstract
- Peptides mimicking the C-terminus of the small subunit (R2) of Mycobacterium tuberculosis ribonucleotide reductase (RNR) can compete for binding to the large subunit (R1) and thus inhibit RNR activity. Moreover, it has been suggested that the binding of the R2 C-terminus is very similar in M. tuberculosis and Salmonella typhimurium. Based on modeling studies of a crystal structure of the holocomplex of the S. typhimurium enzyme, a benzodiazepine-based turn mimetic was identified and a set of novel compounds incorporating the benzodiazepine scaffold was synthesized. The compounds were evaluated in a competitive fluorescence polarization assay and in an RNR activity assay. These studies revealed that the compounds incorporating the benzodiazepine scaffold have the ability to compete for the M. tuberculosis R2 binding site with low-micromolar affinity.
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| 6. |
- de Weerd, Hendrik A., et al.
(författare)
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MODifieR : an ensemble R package for inference of disease modules from transcriptomics networks
- 2020
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Ingår i: Bioinformatics. - : Oxford University Press. - 1367-4803 .- 1367-4811 .- 1460-2059. ; 36:12, s. 3918-3919
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Tidskriftsartikel (refereegranskat)abstract
- MOTIVATION: Complex diseases are due to the dense interactions of many disease-associated factors that dysregulate genes that in turn form so-called disease modules, which have shown to be a powerful concept for understanding pathological mechanisms. There exist many disease module inference methods that rely on somewhat different assumptions, but there is still no gold standard or best performing method. Hence, there is a need for combining these methods to generate robust disease modules.RESULTS: We developed MODule IdentiFIER (MODifieR), an ensemble R package of nine disease module inference methods from transcriptomics networks. MODifieR uses standardized input and output allowing the possibility to combine individual modules generated from these methods into more robust disease-specific modules, contributing to a better understanding of complex diseases.AVAILABILITY: MODifieR is available under the GNU GPL license and can be freely downloaded from https://gitlab.com/Gustafsson-lab/MODifieR and as a Docker image from https://hub.docker.com/r/ddeweerd/modifier.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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| 7. |
- Muthas, Daniel, 1976-
(författare)
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Development and Application of Computational Methods in Antitubercular Drug Design : Identification of Novel Inhibitors of Ribonucleotide Reductase
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis kills approximately 1.7 million people each year around the world making it one of the most lethal infectious diseases. This thesis concerns the development of two computational tools that can support the early stages of drug discovery, and their use in an anti-tubercular drug discovery program. One of the tools developed is a statistical molecular design (SMD) approach that generates information-rich libraries biased towards a lead structure. The other metod is a post-filtering technique to increase the success of virtual screening, has also been developed. Both methods have been validated using literature data. Ribonucleotide reductase (RNR) has been identified as a potential anti-tubercular target, and our focus has been to develop small-molecule inhibitors of this target. The enzyme consists of two subunits (a large R1 and a small R2 subunit) that have to associate in order to generate a bioactive complex. It had previously been shown that a heptapeptide corresponding to the small R2 subunits C-terminal inhibited the enzyme. In order to investigate the requirements for inhibitory effect of the peptide a library was designed using the developed SMD approach. The designed library was synthesized and evaluated for biological activity and an OPLS-DA model was derived to understand which positions were most important for activity. In order to identify small-molecule inhibitors of RNR a combined shape- and structure-based virtual screen was performed, employing ROCS, GlideXP and the developed post-filtering technique. Starting from a library of 1.5 million compounds 24 was acquired and evaluated for enzymatic activity. The best compounds were almost as potent as the starting peptide, but considerably more drug-like.
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| 8. |
- Muthas, Daniel, et al.
(författare)
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Focused hierarchical design of peptide libraries - follow the lead
- 2007
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Ingår i: Journal of Chemometrics. - : Wiley. - 0886-9383 .- 1099-128X. ; 21:10-11, s. 486-495
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Tidskriftsartikel (refereegranskat)abstract
- A novel design strategy based on the hierarchical design of experiments (HDoE) method named focused hierarchical design of experiments (FHDoE) is presented. FHDoE combine two design layers and use focused substitutions to increase the probability of obtaining active peptides when designing libraries through a selection of compounds biased towards a lead structure. Increasing the number of peptides with measurable activity will increase the information gained and the likelihood of constructing good quantitative structure-activity relationship (QSAR) models. The utility of the novel design method is verified using two different approaches. First, a library designed with the novel FHDoE method was compared with libraries generated from classical positional scanning techniques (e.g., alanine scan) as well as with general and centered minimum analog peptide sets (MAPS) libraries by using an example found in the literature. Secondly, the same design strategies were applied to a dataset of 58 angiotensin converting enzyme (ACE) dipeptide inhibitors. QSAR models were generated from designed sublibraries and the activities of the remaining compounds were predicted. These two examples show that the use of FHDoE renders peptide libraries close in physicochemical space to the native ligand, yielding a more thorough screening of the area of interest as compared to the classical positional scans and fractional factorial design (FFD). It is also shown that an FHDoE library of six dipeptides could produce a QSAR model that better described the requisites of high activity ACE inhibitors than could QSAR models built from either a nine-dipeptide library designed with MAPS or a 58-dipeptide library.
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| 9. |
- Muthas, Daniel, et al.
(författare)
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Is it possible to increase hit rates in structure-based virtual screening by pharmacophore filtering? : An investigation of the advantages and pitfalls of post-filtering
- 2008
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Ingår i: Journal of Molecular Graphics and Modelling. - : Elsevier BV. - 1093-3263 .- 1873-4243. ; 26:8, s. 1237-1251
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the influence of post-filtering virtual screening results, with pharmacophoric features generated from an X-ray structure, on enrichment rates. This was performed using three docking softwares, zdock+, Surflex and FRED, as virtual screening tools and pharmacophores generated in UNITY from co-crystallized complexes. Sets of known actives along with 9997 pharmaceutically relevant decoy compounds were docked against six chemically diverse protein targets namely CDK2, COX2, ERalpha, fXa, MMP3, and NA. To try to overcome the inherent limitations of the well-known docking problem, we generated multiple poses for each compound. The compounds were first ranked according to their scores alone and enrichment rates were calculated using only the top scoring pose of each compound. Subsequently, all poses for each compound were passed through the different pharmacophores generated from co-crystallized complexes and the enrichment factors were re-calculated based on the top-scoring passing pose of each compound. Post-filtering with a pharmacophore generated from only one X-ray complex was shown to increase enrichment rates in all investigated targets compared to docking alone. This indicates that this is a general method, which works for diverse targets and different docking softwares.
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| 10. |
- Nordqvist, Anneli, et al.
(författare)
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Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
- 2012
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 3:5, s. 620-626
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Tidskriftsartikel (refereegranskat)abstract
- Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.
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