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Muthas, Daniel
Publications (3 of 3) Show all publications
Nurbo, J., Roos, A. K., Muthas, D., Wahlström, E., Ericsson, D. J., Lundstedt, T., . . . Karlén, A. (2007). Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase. Journal of Peptide Science, 13(12), 822-832
Open this publication in new window or tab >>Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
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2007 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 12, p. 822-832Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
mycobacterium tuberculosis, ribonucleotide reductase, peptide inhibitors, alanine scan, statistical molecular design, structure activity relationships, FHDoE
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-14261 (URN)10.1002/psc.906 (DOI)000252000600007 ()17918768 (PubMedID)
Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-01-12Bibliographically approved
Muthas, D., Lek, P. M., Nurbo, J., Karlén, A. & Lundstedt, T. (2007). Focused hierarchical design of peptide libraries - follow the lead. Journal of Chemometrics, 21(10-11), 486-495
Open this publication in new window or tab >>Focused hierarchical design of peptide libraries - follow the lead
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2007 (English)In: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 21, no 10-11, p. 486-495Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
design of experiments, peptide library design, hierarchical design, amino acid z-scales, PCA
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-17025 (URN)10.1002/cem.1069 (DOI)000250873300009 ()
Available from: 2008-06-15 Created: 2008-06-15 Last updated: 2018-01-12Bibliographically approved
Muthas, D., Nötteberg, D., Sabnis, Y. A., Hamelink, E., Vrang, L., Samuelsson, B., . . . Hallberg, A. (2005). Synthesis, biological evaluation, and modeling studies of inhibitors aimed at the malarial proteases plasmepsins I and II.. Bioorg Med Chem, 13(18), 5371-90
Open this publication in new window or tab >>Synthesis, biological evaluation, and modeling studies of inhibitors aimed at the malarial proteases plasmepsins I and II.
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2005 (English)In: Bioorg Med Chem, ISSN 0968-0896, Vol. 13, no 18, p. 5371-90Article in journal (Refereed) Published
Keywords
Animals, Antimalarials/*chemical synthesis/chemistry/*pharmacology, Aspartic Endopeptidases/*antagonists & inhibitors, Computer Simulation, Models; Biological, Models; Molecular, Plasmodium falciparum/enzymology, Protease Inhibitors/chemical synthesis/chemistry/*pharmacology, Quantitative Structure-Activity Relationship, Research Support; Non-U.S. Gov't
Identifiers
urn:nbn:se:uu:diva-75615 (URN)16054370 (PubMedID)
Available from: 2006-02-13 Created: 2006-02-13 Last updated: 2011-01-11
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