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Oliveira, Ana
Publications (7 of 7) Show all publications
Ge, X., Oliveira, A., Hjort, K., Bergfors, T., Gutiérrez-de-Terán, H., Andersson, D. I., . . . Åqvist, J. (2019). Inhibition of translation termination by small molecules targeting ribosomal release factors. Scientific Reports, 9, Article ID 15424.
Open this publication in new window or tab >>Inhibition of translation termination by small molecules targeting ribosomal release factors
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 15424Article in journal (Refereed) Published
Abstract [en]

The bacterial ribosome is an important drug target for antibiotics that can inhibit different stages of protein synthesis. Among the various classes of compounds that impair translation there are, however, no known small-molecule inhibitors that specifically target ribosomal release factors (RFs). The class I RFs are essential for correct termination of translation and they differ considerably between bacteria and eukaryotes, making them potential targets for inhibiting bacterial protein synthesis. We carried out virtual screening of a large compound library against 3D structures of free and ribosome-bound RFs in order to search for small molecules that could potentially inhibit termination by binding to the RFs. Here, we report identification of two such compounds which are found both to bind free RFs in solution and to inhibit peptide release on the ribosome, without affecting peptide bond formation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Medicinal Chemistry Structural Biology
Identifiers
urn:nbn:se:uu:diva-396310 (URN)10.1038/s41598-019-51977-1 (DOI)000492832300009 ()31659219 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish National Infrastructure for Computing (SNIC)
Available from: 2019-11-01 Created: 2019-11-01 Last updated: 2019-11-18Bibliographically approved
Vasile, S., Esguerra, M., Jespers, W., Oliveira, A., Sallander, J., Åqvist, J. & Gutiérrez-de-Terán, H. (2018). Characterization of Ligand Binding to GPCRs Through Computational Methods.. In: Computational Methods for GPCR Drug Discovery: (pp. 23-44). New York, NY: Humana Press, 1705
Open this publication in new window or tab >>Characterization of Ligand Binding to GPCRs Through Computational Methods.
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2018 (English)In: Computational Methods for GPCR Drug Discovery, New York, NY: Humana Press, 2018, Vol. 1705, p. 23-44Chapter in book (Refereed)
Abstract [en]

The recent increase in available G protein-coupled receptor structures now contributes decisively to the structure-based ligand design. In this context, computational approaches in combination with medicinal chemistry and pharmacology are extremely helpful. Here, we provide an update on our structure-based computational protocols, used to answer key questions related to GPCR-ligand binding. All combined, these techniques can shed light on ligand binding modes, determine the molecular basis of conformational selection, for agonists and antagonists, as well as of subtype selectivity. To illustrate each of these questions, we will consider examples from existing projects on three families of class A (rhodopsin-like) GPCRs: one small-molecule (nucleotide-like) family, i.e., the adenosine receptors, and two peptide-binding receptors: neuropeptide-Y and angiotensin II receptors. The successful application of the same computational protocols to investigate this diverse group of receptor families gives an idea of the general applicability of our methodology in the characterization of GPCR-ligand binding.

Place, publisher, year, edition, pages
New York, NY: Humana Press, 2018
Keywords
Free energy perturbation, Homology modeling, Molecular dynamics, Structure-based drug design
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-395745 (URN)10.1007/978-1-4939-7465-8_2 (DOI)29188557 (PubMedID)
Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2020-01-22Bibliographically approved
Carbajales, C., Azuaje, J., Oliveira, A., Loza, M. I., Brea, J., Cadavid, M. I., . . . Sotelo, E. (2017). Enantiospecific Recognition at the A(2B) Adenosine Receptor by Alkyl 2-Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates. Journal of Medicinal Chemistry, 60(8), 3372-3382
Open this publication in new window or tab >>Enantiospecific Recognition at the A(2B) Adenosine Receptor by Alkyl 2-Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates
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2017 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 8, p. 3372-3382Article in journal (Refereed) Published
Abstract [en]

A novel family of structurally simple, potent, and selective nonxanthine A(2B)AR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(+/-)16b, K-i = 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A(2B)AR, with the (S)-16b enantiomer retaining all the affinity (K-i = 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A(2B) adenosine receptor and opens new possibilities in ligand design for this receptor.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-323455 (URN)10.1021/acs.jmedchem.7b00138 (DOI)000400538900011 ()28368607 (PubMedID)
Funder
Swedish Research CouncileSSENCE - An eScience Collaboration
Available from: 2017-06-07 Created: 2017-06-07 Last updated: 2018-01-13Bibliographically approved
Lind, C., Oliveira, A. & Åqvist, J. (2017). Origin of the omnipotence of eukaryotic release factor 1. Nature Communications, 8, Article ID 1425.
Open this publication in new window or tab >>Origin of the omnipotence of eukaryotic release factor 1
2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 1425Article in journal (Refereed) Published
Abstract [en]

Termination of protein synthesis on the ribosome requires that mRNA stop codons are recognized with high fidelity. This is achieved by specific release factor proteins that are very different in bacteria and eukaryotes. Hence, while there are two release factors with overlapping specificity in bacteria, the single omnipotent eRF1 release factor in eukaryotes is able to read all three stop codons. This is particularly remarkable as it is able to select three out of four combinations of purine bases in the last two codon positions. With recently determined 3D structures of eukaryotic termination complexes, it has become possible to explore the origin of eRF1 specificity by computer simulations. Here, we report molecular dynamics free energy calculations on these termination complexes, where relative eRF1 binding free energies to different cognate and near-cognate codons are evaluated. The simulations show a high and uniform discrimination against the near-cognate codons, that differ from the cognate ones by a single nucleotide, and reveal the structural mechanisms behind the precise decoding by eRF1.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-328582 (URN)10.1038/s41467-017-01757-0 (DOI)000414869900011 ()29127299 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish National Infrastructure for Computing (SNIC)
Available from: 2017-08-27 Created: 2017-08-27 Last updated: 2018-02-26Bibliographically approved
Hamnevik, E., Enugala, T. R., Maurer, D., Ntuku, S., Oliveira, A., Dobritzsch, D. & Widersten, M. (2017). Relaxation of Nonproductive Binding and Increased Rate of Coenzyme Release in an Alcohol Dehydrogenase Increases Turnover With a Non-Preferred Alcohol Enantiomer. The FEBS Journal, 284(22), 3895-3914
Open this publication in new window or tab >>Relaxation of Nonproductive Binding and Increased Rate of Coenzyme Release in an Alcohol Dehydrogenase Increases Turnover With a Non-Preferred Alcohol Enantiomer
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2017 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 284, no 22, p. 3895-3914Article in journal (Refereed) Published
Abstract [en]

Alcohol dehydrogenase A (ADH-A) from Rhodococcus ruber DSM 44541 is a promising biocatalyst for redox transformations of arylsubstituted sec-alcohols and ketones. The enzyme is stereoselective in the oxidation of 1-phenylethanol with a 300-fold preference for the (S)-enantiomer. The low catalytic efficiency with (R)-1-phenylethanol has been attributed to nonproductive binding of this substrate at the active site. Aiming to modify the enantioselectivity, to rather favor the (R)-alcohol, and also test the possible involvement of nonproductive substrate binding as a mechanism in substrate discrimination, we performed directed laboratory evolution of ADH-A. Three targeted sites that contribute to the active-site cavity were exposed to saturation mutagenesis in a stepwise manner and the generated variants were selected for improved catalytic activity with (R)-1-phenylethanol. After three subsequent rounds of mutagenesis, selection and structure-function analysis of isolated ADH-A variants, we conclude: (1) W295 has a key role as a structural determinant in the discrimination between (R)- and (S)-1-phenylethanol and a W295A substitution fundamentally changes the stereoselectivity of the protein. One observable effect is a faster rate of NADH release, which changes the rate-limiting step of the catalytic cycle from coenzyme release to hydride transfer. (2) The obtained change in enantiopreference, from the (S)- to the (R)-alcohol, can be partly explained by a shift in the nonproductive substrate binding modes.

Keywords
alcohol dehydrogenase, biocatalysis, stereoselectivity, directed evolution, crystal structures, enzyme kinetics
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-318981 (URN)10.1111/febs.14279 (DOI)000415877100011 ()
Funder
Swedish Research Council, 621-2011-6055
Available from: 2017-03-30 Created: 2017-03-30 Last updated: 2019-10-21Bibliographically approved
Jespers, W., Oliveira, A., Prieto-Diaz, R., Majellaro, M., Åqvist, J., Sotelo, E. & Gutiérrez-de-Terán, H. (2017). Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors. Molecules, 22(11), Article ID 1945.
Open this publication in new window or tab >>Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors
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2017 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 11, article id 1945Article in journal (Refereed) Published
Abstract [en]

The four receptors that signal for adenosine, A(1), A(2A), A(2B) and A(3) ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A(2A), and lately the A(1) ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs. We herein review and update the results of this program with particular focus on molecular dynamics (MD) and free energy perturbation (FEP) protocols. The first in silico mutagenesis on the A(1)AR here reported allows understanding the specificity and high affinity of the xanthine-antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). On the A(2A)AR, we demonstrate how FEP simulations can distinguish the conformational selectivity of a recent series of partial agonists. These novel results are complemented with the revision of the first series of enantiospecific antagonists on the A(2B)AR, and the use of FEP as a tool for bioisosteric design on the A(3)AR.

Place, publisher, year, edition, pages
MDPI AG, 2017
Keywords
free energy perturbation (FEP), G protein-coupled receptors (GPCRs), molecular dynamics (MD) simulations, structure-based drug design (SBDD)
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-344330 (URN)10.3390/molecules22111945 (DOI)000416528400145 ()
Funder
Swedish Research Council, 521-2014-2118eSSENCE - An eScience CollaborationEuropean Regional Development Fund (ERDF)
Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-03-09Bibliographically approved
Bharate, S. B., Singh, B., Kachler, S., Oliveira, A., Kumar, V., Bharate, S. S., . . . de Teran, H. G. (2016). Discovery of 7-(Prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A(2A) Adenosine Receptor: Prediction from Molecular Modeling. Journal of Medicinal Chemistry, 59(12), 5922-5928
Open this publication in new window or tab >>Discovery of 7-(Prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A(2A) Adenosine Receptor: Prediction from Molecular Modeling
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2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 12, p. 5922-5928Article in journal (Refereed) Published
Abstract [en]

We describe the identification of 7-(prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A(2A) adenosine receptor (A(2A)AR). Molecular-modeling indicated that the (S)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists' ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A(2A)AR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-299890 (URN)10.1021/acs.jmedchem.6b00552 (DOI)000378662900027 ()27227326 (PubMedID)
Available from: 2016-08-01 Created: 2016-07-29 Last updated: 2018-01-10Bibliographically approved
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