| 1. |
- Honarparvar, Bahareh, et al.
(författare)
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Pentacycloundecane-diol-Based HIV-1 Protease Inhibitors : Biological Screening, 2D NMR, and Molecular Simulation Studies
- 2012
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:6, s. 1009-1019
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Tidskriftsartikel (refereegranskat)abstract
- Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC50 values in the 0.50.6 mu M range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space 1H,1H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.
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| 2. |
- Malo, Marcus, et al.
(författare)
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Investigation of D1 receptor-agonist interactions and D1/D2 agonist selectivity using a combination of pharmacophore and receptor homology modelling
- 2012
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 483-494
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist-bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand-interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.
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| 3. |
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| 4. |
- Sehgelmeble, Fernando, et al.
(författare)
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Sulfonimidamides as Sulfonamides Bioisosteres : Rational Evaluation through Synthetic, in Vitro, and in Vivo Studies with γ-Secretase Inhibitors
- 2012
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 396-399
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Tidskriftsartikel (refereegranskat)abstract
- The proof of the pudding: A proof-of-concept study using γ-secretase inhibitors as a model has shown that sulfonimidamides act as bioisosteres for sulfonamides. Detailed in vitro and in vivo profiling reveal that the sulfonimidamide motif imparts desirable properties such as decreased lipophilicity and plasma protein binding, accompanied by increased solubility. Our data support a wider use of this unique functional group in the design of new pharmacologically active agents.
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| 5. |
- Wacker, Soeren J., et al.
(författare)
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Identification of Selective Inhibitors of the Potassium Channel Kv1.1-1.2(3) by High-Throughput Virtual Screening and Automated Patch Clamp
- 2012
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:10, s. 1775-1783
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Tidskriftsartikel (refereegranskat)abstract
- Two voltage-dependent potassium channels, Kv1.1 (KCNA1) and Kv1.2 (KCNA2), are found to co-localize at the juxtaparanodal region of axons throughout the nervous system and are known to co-assemble in heteromultimeric channels, most likely in the form of the concatemer Kv1.11.2(3). Loss of the myelin sheath, as is observed in multiple sclerosis, uncovers the juxtaparanodal region of nodes of Ranvier in myelinated axons leading to potassium conductance, resulting in loss of nerve conduction. The selective blocking of these Kv channels is therefore a promising approach to restore nerve conduction and function. In the present study, we searched for novel inhibitors of Kv1.11.2(3) by combining a virtual screening protocol and electrophysiological measurements on a concatemer Kv1.11.2(3) stably expressed in Chinese hamster ovary K1 (CHO-K1) cells. The combined use of four popular virtual screening approaches (eHiTS, FlexX, Glide, and Autodock-Vina) led to the identification of several compounds as potential inhibitors of the Kv1.11.2(3) channel. From 89 electrophysiologically evaluated compounds, 14 novel compounds were found to inhibit the current carried by Kv1.11.2(3) channels by more than 80?% at 10 mu M. Accordingly, the IC50 values calculated from concentrationresponse curve titrations ranged from 0.6 to 6 mu M. Two of these compounds exhibited at least 30-fold higher potency in inhibition of Kv1.11.2(3) than they showed in inhibition of a set of cardiac ion channels (hERG, Nav1.5, and Cav1.2), resulting in a profile of selectivity and cardiac safety. The results presented herein provide a promising basis for the development of novel selective ion channel inhibitors, with a dramatically lower demand in terms of experimental time, effort, and cost than a sole high-throughput screening approach of large compound libraries.
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| 6. |
- Xia, Xin, et al.
(författare)
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In vivo Enhancement in Bioavailability of Atazanavir in the Presence of Proton-Pump Inhibitors using Mesoporous Materials
- 2012
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:1, s. 43-8
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Tidskriftsartikel (refereegranskat)abstract
- Matters of the HAART! The current treatment for human immunodeficiency virus (HIV), HAART, makes use of a combination of antiretroviral drugs, which are poorly soluble in aqueous media. Enhancing the solubility of such drugs through the use of mesoporous materials could lead to improved treatment efficiency and might provide a solution to the drug-drug interaction problems associated with these types of therapeutic regimes.
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