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Gutiérrez-de-Terán, HugoORCID iD iconorcid.org/0000-0003-0459-3491
Alternative names
Publications (10 of 58) Show all publications
Jespers, W., Åqvist, J. & Gutiérrez-de-Terán, H. (2020). Free energy calculations for protein-ligand binding prediction. In: Protein-Ligand Interactions and Drug Design: . Springer Nature
Open this publication in new window or tab >>Free energy calculations for protein-ligand binding prediction
2020 (English)In: Protein-Ligand Interactions and Drug Design, Springer Nature, 2020Chapter in book (Other academic)
Place, publisher, year, edition, pages
Springer Nature, 2020
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-407846 (URN)
Available from: 2020-03-30 Created: 2020-03-30 Last updated: 2020-05-20
Engen, K., Reddy Vanga, S., Lundbäck, T., Agalo, F., Konda, V., Jensen, A. J., . . . Rosenström, U. (2020). Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors. ChemistryOpen, 9(3), 325-337
Open this publication in new window or tab >>Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors
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2020 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 9, no 3, p. 325-337Article in journal (Refereed) Published
Abstract [en]

Insulin‐regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non‐peptide IRAP inhibitors derived from a spiro‐oxindole dihydroquinazolinone screening hit (pIC50 5.8). The compounds were synthesized either by a simple microwave (MW)‐promoted three‐component reaction, or by a two‐step one‐pot procedure. For decoration of the oxindole ring system, rapid MW‐assisted Suzuki‐Miyaura cross‐couplings (1 min) were performed. A small improvement of potency (pIC50 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S‐configuration of the spiro‐oxindole dihydroquinazolinones accounts for the inhibition of IRAP.

Keywords
enzymes, inhibitors, insulin, preclinical profiling, regulated aminopeptidases, spiro compounds
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-406132 (URN)10.1002/open.201900344 (DOI)000522554000007 ()32154052 (PubMedID)
Available from: 2020-03-05 Created: 2020-03-05 Last updated: 2020-05-07Bibliographically approved
Isaksson, R., Lindman, J., Wannberg, J., Sallander, J., Backlund, M., Baraldi, D., . . . Larhed, M. (2019). A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode. ChemistryOpen, 8(1), 114-125
Open this publication in new window or tab >>A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
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2019 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 8, no 1, p. 114-125Article in journal (Refereed) Published
Abstract [en]

We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.

National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-377050 (URN)10.1002/open.201800282 (DOI)000457433000017 ()30697513 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC)Swedish Research Council
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-04-04Bibliographically approved
Lind, C., Esguerra, M., Jespers, W., Satpati, P., Gutiérrez-de-Terán, H. & Åqvist, J. (2019). Free energy calculations of RNA interactions. Methods, 162-163, 85-95
Open this publication in new window or tab >>Free energy calculations of RNA interactions
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2019 (English)In: Methods, ISSN 1046-2023, E-ISSN 1095-9130, Vol. 162-163, p. 85-95Article in journal (Refereed) Published
Abstract [en]

This review discusses the use of molecular dynamics free energy calculations for characterizing RNA interactions, with particular emphasis on molecular recognition events involved in mRNA translation on the ribosome. The general methodology for efficient free energy calculations is outlined and our specific implementation for binding free energy changes due to base mutations in mRNA and tRNA is described, We show that there are a number of key problems related to the accuracy of protein synthesis that can be addressed with this type of computational approach and several such examples are discussed in detail. These include the decoding of mRNA during peptide chain elongation, initiation and termination of translation, as well as the energetic effects of base tautomerization and tRNA modifications. It is shown that free energy calculations can be made sufficiently reliable to allow quantitative conclusions to be drawn regarding the energetics of cognate versus non-cognate interactions and its structural origins.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Free energy calculation, Molecular dynamics, RNA interactions, Ribosome, mRNA translation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-390696 (URN)10.1016/j.ymeth.2019.02.014 (DOI)000475837300011 ()30794905 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish National Infrastructure for Computing (SNIC)
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-13Bibliographically approved
Jandova, Z., Jespers, W., Sotelo, E., Gutiérrez-de-Terán, H. & Oostenbrink, C. (2019). Free-Energy Calculations for Bioisosteric Modifications of A(3) Adenosine Receptor Antagonists. International Journal of Molecular Sciences, 20(14), Article ID 3499.
Open this publication in new window or tab >>Free-Energy Calculations for Bioisosteric Modifications of A(3) Adenosine Receptor Antagonists
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2019 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 14, article id 3499Article in journal (Refereed) Published
Abstract [en]

Adenosine receptors are a family of G protein-coupled receptors with increased attention as drug targets on different indications. We investigate the thermodynamics of ligand binding to the A(3) adenosine receptor subtype, focusing on a recently reported series of diarylacetamidopyridine inhibitors via molecular dynamics simulations. With a combined approach of thermodynamic integration and one-step perturbation, we characterize the impact of the charge distribution in a central heteroaromatic ring on the binding affinity prediction. Standard charge distributions according to the GROMOS force field yield values in good agreement with the experimental data and previous free energy calculations. Subsequently, we examine the thermodynamics of inhibitor binding in terms of the energetic and entropic contributions. The highest entropy penalties are found for inhibitors with methoxy substituents in meta position of the aryl groups. This bulky group restricts rotation of aromatic rings attached to the pyrimidine core which leads to two distinct poses of the ligand. Our predictions support the previously proposed binding pose for the o-methoxy ligand, yielding in this case a very good correlation with the experimentally measured affinities with deviations below 4 kJ/mol.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
Adenosine receptor, free energy calculations, molecular dynamics simulations, Groningen Molecular Simulation packace (GROMOS)
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:uu:diva-393635 (URN)10.3390/ijms20143499 (DOI)000480449300123 ()31315296 (PubMedID)
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved
Shebanits, K., Vasile, S., Xu, B., Gutiérrez-de-Terán, H. & Larhammar, D. (2019). Functional characterization in vitro of twelve naturally occurring variants of the human pancreatic polypeptide receptor NPY4R. Neuropeptides, 76, Article ID 101933.
Open this publication in new window or tab >>Functional characterization in vitro of twelve naturally occurring variants of the human pancreatic polypeptide receptor NPY4R
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2019 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 76, article id 101933Article in journal (Refereed) Published
Abstract [en]

Obesity has become a global health problem and therefore understanding of the mechanisms regulating hunger and satiety is of utmost importance for the development of new treatment strategies. The Y4 receptor, encoded by the NPY4R gene, and its ligand pancreatic polypeptide (PP) have been reported to mediate a satiety signal. Multiple genetic studies have reported an association between NPY4R copy number and body weight. The gene also displays several SNP variants, many of which lead to amino acid differences, making it interesting to study. We have investigated the functional properties of 12 naturally occurring amino acid sequence variants of the Y4 and interpret the results in relation to sequence conservation and our structural model of the human Y4 receptor protein. Three receptor variants, Cys201ECL2Tyr, Val2716.41Leu and Asn3187.49Asp, were found to completely lose functional response, measured as inositol phosphate turnover, while retaining membrane expression. They display high sequence conservation and have important roles in the receptor structure. For two receptor variants the potency of PP was significantly decreased, Cys34NTSer (EC50 = 2.9 nM, p < .001) and Val1353.46Met (EC50 = 3.0 nM, p < .01), compared to wild-type Y4 (EC50 = 0.68 nM). Cys34 forms a disulphide bond with Cys298, linking the N-terminal part to ECL3. The Val1353.46Met variant has an amino acid replacement located in the TM3 helix, one helix turn above the highly conserved ERH motif. This position has influence on the network of residues involved in receptor activation and subsequent inactivation. Sequence conservation and the structural model are consistent with these results. The remaining seven positions had no significant effect on the receptor's functional response compared to wild-type Y4. These positions display more variation during evolution. Understanding of the interactions between the Y4 receptor and its native PP agonist and the effects of amino acid variation on its functional response will hopefully lead to future therapeutic possibilities.

Keywords
Y4, SNP, Mutagenesis, Functional pharmacology, Structural modelling
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-356572 (URN)10.1016/j.npep.2019.05.004 (DOI)000482249700004 ()31230758 (PubMedID)
Funder
Swedish Research Council, K2013-55 x -22189-01-2The Swedish Brain Foundation, F02016-0217
Available from: 2018-08-01 Created: 2018-08-01 Last updated: 2019-12-06Bibliographically approved
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
Jespers, W., Esguerra, M., Åqvist, J. & Gutiérrez-de-Terán, H. (2019). QligFEP: an automated workflow for small molecule free energy calculations in Q. Journal of Cheminformatics, 11, Article ID 26.
Open this publication in new window or tab >>QligFEP: an automated workflow for small molecule free energy calculations in Q
2019 (English)In: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 11, article id 26Article in journal (Refereed) Published
Abstract [en]

The process of ligand binding to a biological target can be represented as the equilibrium between the relevant solvated and bound states of the ligand. This which is the basis of structure-based, rigorous methods such as the estimation of relative binding affinities by free energy perturbation (FEP). Despite the growing capacity of computing power and the development of more accurate force fields, a high throughput application of FEP is currently hampered due to the need, in the current schemes, of an expert user definition of the alchemical transformations between molecules in the series explored. Here, we present QligFEP, a solution to this problem using an automated workflow for FEP calculations based on a dual topology approach. In this scheme, the starting poses of each of the two ligands, for which the relative affinity is to be calculated, are explicitly present in the MD simulations associated with the (dual topology) FEP transformation, making the perturbation pathway between the two ligands univocal. We show that this generalized method can be applied to accurately estimate solvation free energies for amino acid sidechain mimics, as well as the binding affinity shifts due to the chemical changes typical of lead optimization processes. This is illustrated in a number of protein systems extracted from other FEP studies in the literature: inhibitors of CDK2 kinase and a series of A(2A) adenosine G protein-coupled receptor antagonists, where the results obtained with QligFEP are in excellent agreement with experimental data. In addition, our protocol allows for scaffold hopping perturbations to identify the binding affinities between different core scaffolds, which we illustrate with a series of Chk1 kinase inhibitors. QligFEP is implemented in the open-source MD package Q, and works with the most common family of force fields: OPLS, CHARMM and AMBER.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Free energy perturbation (FEP), Molecular dynamics (MD), Ligand binding, Application programming interface (API), Dual topology
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-382389 (URN)10.1186/s13321-019-0348-5 (DOI)000463589200001 ()30941533 (PubMedID)
Funder
Swedish Research CouncileSSENCE - An eScience Collaboration
Available from: 2019-04-26 Created: 2019-04-26 Last updated: 2020-03-30Bibliographically approved
Jespers, W., Isaksen, G. V., Andberg, T. A., Vasile, S., van Veen, A., Åqvist, J., . . . Gutiérrez-de-Terán, H. (2019). QresFEP: An Automated Protocol for Free Energy Calculations of Protein Mutations in Q. Journal of Chemical Theory and Computation, 15(10), 5461-5473
Open this publication in new window or tab >>QresFEP: An Automated Protocol for Free Energy Calculations of Protein Mutations in Q
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2019 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 15, no 10, p. 5461-5473Article in journal (Refereed) Published
Abstract [en]

Predicting the effect of single-point mutations on protein stability or protein-ligand binding is a major challenge in computational biology. Free energy calculations constitute the most rigorous approach to this problem, though the estimation of converged values for amino acid mutations remains challenging. To overcome this limitation, we developed tailored protocols to calculate free energy shifts associated with single-point mutations. We herein describe the QresFEP protocol, which includes an extension of our recent protocols to cover all amino acids mutations, based on the latest versions of the OPLS-AA force field. QresFEP is implemented in an application programming interface framework and the graphic interface QGui, for the molecular dynamics software Q. The complete protocol is benchmarked in several model systems, optimizing a number of sampling parameters and the implementation of Zwanzig's exponential formula and Bennet's acceptance ratio methods. QresFEP shows an excellent performance on estimating the hydration free energies of amino acid side-chain mimics, including their charged analogues. We also examined its performance on a protein-ligand binding problem of pharmaceutical relevance, the antagonism of neuropeptide Y1 G protein-coupled receptor. Here, the calculations show very good agreement with the experimental effect of 16 mutations on the binding of antagonists BIBP3226, in line with our recent applications in this field. Finally, the characterization of 43 mutations of T4-lysozyme reveals the capacity of our protocol to assess variations of the thermal stability of proteins, achieving a similar performance to alternative free energy perturbation (FEP) approaches. In summary, QresFEP is a robust, versatile, and user-friendly computational FEP protocol to examine biochemical effects of single-point mutations with high accuracy.

National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-395642 (URN)10.1021/acs.jctc.9b00538 (DOI)000489678700026 ()31436990 (PubMedID)
Funder
The Research Council of Norway, 262695 274858Swedish Research CouncilKnut and Alice Wallenberg FoundationeSSENCE - An eScience Collaboration
Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2020-03-30Bibliographically approved
Mallo-Abreu, A., Majellaro, M., Jespers, W., Azuaje, J., Caamano, O., Garcia-Mera, X., . . . Sotele, E. (2019). Trifluorinated Pyrimidine-Based A(2B) Antagonists: Optimization and Evidence of Stereospecific Recognition. Journal of Medicinal Chemistry, 62(20), 9315-9330
Open this publication in new window or tab >>Trifluorinated Pyrimidine-Based A(2B) Antagonists: Optimization and Evidence of Stereospecific Recognition
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2019 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 20, p. 9315-9330Article in journal (Refereed) Published
Abstract [en]

We report the identification of two subsets of fluorinated nonxanthine A(2B) adenosine receptor antagonists. The novel derivatives explore the effect of fluorination at different positions of two pyrimidine-based scaffolds. The most interesting ligands combine excellent hA(2B) affinity (K-i < 15 nM) and remarkable subtype selectivity. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The compounds were designed on the basis of previous molecular models of the stereoselective binding of the parent scaffolds to the hA(2B) receptor, and we herein provide refinement of such models with the fluorinated compounds, which allows the explanation of the spurious effects of the fluorination at the different positions explored. These models are importantly confirmed by a synergistic study combining chiral HPLC, circular dichroism, diastereoselective synthesis, molecular modeling, and X-ray crystallography, providing experimental evidence toward the stereospecific interaction between optimized trifluorinated stereoisomers and the hA(2B) receptor.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2019
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-396965 (URN)10.1021/acs.jmedchem.9b01340 (DOI)000492801800027 ()31557025 (PubMedID)
Funder
Swedish Research CouncileSSENCE - An eScience Collaboration
Available from: 2019-11-13 Created: 2019-11-13 Last updated: 2020-03-30Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-0459-3491

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