| 1. |
- Isaksson, Rebecka, et al.
(author)
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A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
- 2019
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In: ChemistryOpen. - : Wiley. - 2191-1363. ; 8:1, s. 114-125
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Journal article (peer-reviewed)abstract
- 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.
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| 2. |
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| 3. |
- Ersmark, Karolina, et al.
(author)
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C2-symmetric inhibitors of Plasmodium falciparum plasmepsin II : synthesis and theoretical predictions
- 2003
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In: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:17, s. 3723-3733
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Journal article (peer-reviewed)abstract
- A series of C(2)-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography. Within both series of isomers the theoretical binding energies were in agreement with the enzymatic measurements, illustrating the power of the LIE method for the prediction of ligand affinities prior to synthesis. The structural models of the enzyme-inhibitor complexes obtained from the MD simulations provided a basis for interpretation of further structure-activity relationships. Hence, the affinity of a structurally similar ligand, but with a different P2/P2' substituent was examined using the same procedure. The predicted improvement in binding constant agreed well with experimental results.
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| 5. |
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| 6. |
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| 7. |
- Hultén, Johan, et al.
(author)
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Cyclic HIV-1 protease inhibitors derived from mannitol : synthesis, inhibitory potencies, and computational predictions of binding affinities
- 1997
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40:6, s. 885-897
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Journal article (peer-reviewed)abstract
- Ten C-2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (la and 2-5). Thirdly, compounds with hydrogen bond-accepting or -donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.
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| 8. |
- Lind, Christoffer, et al.
(author)
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Codon-reading specificities of mitochondrial release factors and translation termination at non-standard stop codons
- 2013
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 4
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Journal article (peer-reviewed)abstract
- A key feature of mitochondrial translation is the reduced number of transfer RNAs and reassignment of codons. For human mitochondria, a major unresolved problem is how the set of stop codons are decoded by the release factors mtRF1a and mtRF1. Here we present three-dimensional structural models of human mtRF1a and mtRF1 based on their homology to bacterial RF1 in the codon recognition domain, and the strong conservation between mitochondrial and bacterial ribosomal RNA in the decoding region. Sequence changes in the less homologous mtRF1 appear to be correlated with specific features of the mitochondrial rRNA. Extensive computer simulations of the complexes with the ribosomal decoding site show that both mitochondrial factors have similar specificities and that neither reads the putative vertebrate stop codons AGA and AGG. Instead, we present a structural model for a mechanism by which the ICT1 protein causes termination by sensing the presence of these codons in the A-site of stalled ribosomes.
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| 9. |
- Mishra, Sushil Kumar, et al.
(author)
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Computational prediction of monosaccharide binding free energies to lectins with linear interaction energy models
- 2012
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In: Journal of Computational Chemistry. - : Wiley. - 0192-8651 .- 1096-987X. ; 33:29, s. 2340-2350
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Journal article (peer-reviewed)abstract
- The linear interaction energy (LIE) method to compute binding free energies is applied to lectin-monosaccharide complexes. Here, we calculate the binding free energies of monosaccharides to the Ralstonia solanacearum lectin (RSL) and the Pseudomonas aeruginosa lectin-II (PA-IIL). The standard LIE model performs very well for RSL, whereas the PA-IIL system, where ligand binding involves two calcium ions, presents a major challenge. To overcome this, we explore a new variant of the LIE model, where ligandmetal ion interactions are scaled separately. This model also predicts the saccharide binding preference of PA-IIL on mutation of the receptor, which may be useful for protein engineering of lectins.
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| 10. |
- Satpati, Priyadarshi, et al.
(author)
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Structure-Based Energetics of mRNA Decoding on the Ribosome
- 2014
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In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 53:10, s. 1714-1722
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Journal article (peer-reviewed)abstract
- The origin of high fidelity in bacterial protein synthesis on the ribosome remains a fundamental unsolved problem despite available three-dimensional structures of different stages of the translation process. However, these structures open up the possibility of directly computing the energetics of tRNA selection that is required for an authentic understanding of fidelity in decoding. Here, we report extensive computer simulations that allow us to quantitatively calculate tRNA discrimination and uncover the energetics underlying accuracy in code translation. We show that the tRNA-mRNA interaction energetics varies drastically along the path from initial selection to peptide bond formation. While the selection process is obviously controlled by kinetics, the underlying thermodynamics explains the origin of the high degree of accuracy. The existence of both low- and high-selectivity states provides an efficient mechanism for initial selection and proofreading that does not require codon-dependent long-range structural signaling within the ribosome. It is instead the distinctly unequal population of the high-selectivity states for cognate and noncognate substrates that is the key discriminatory factor. The simulations reveal the essential roles played both by the 30S subunit conformational switch and by the common tRNA modification at position 37 in amplifying the accuracy.
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