| 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. |
- Mahmoud, Sayed, et al.
(författare)
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Non-linear behaviour of base-isolated building supported on flexible soil under damaging earthquakes
- 2012
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Ingår i: Advances in Fracture and Damage Mechanics X. - 1013-9826. ; 488-489, s. 142-145
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Konferensbidrag (refereegranskat)abstract
- Seismic isolation is a strategy to reduce damage of structures exposed to devastating earthquake excitations. Isolation systems, applied at the base of buildings, lower the fundamental frequency of the structure below the range of dominant frequencies of the ground motion as well as allow to dissipate more energy during structural vibrations. The effectiveness of the base-isolated buildings in damage reduction has been confirmed numerically for the models of structures with fixed supports. The aim of the present paper is to show the results of the non-linear analysis of the response of a base-isolated building supported on soft soil incorporating soil-structure interaction. The detailed study has been conducted for the building equipped with high damping rubber bearings used as isolation devices. The results of numerical simulations demonstrate that soil flexibility has a significant influence on the behaviour of isolated base of the structure. Considering the flexibility of soil significantly affects the rigid superstructure response lowering its potential to reduce structural damage.
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| 3. |
- Mahmoud, Sayed, et al.
(författare)
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Simulation of the response of base-isolated buildings under earthquake excitations considering soil flexibility
- 2012
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Ingår i: Earthquake Engineering and Engineering Vibration. - : Springer Science and Business Media LLC. - 1671-3664 .- 1993-503X. ; 11:3, s. 359-374
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Tidskriftsartikel (refereegranskat)abstract
- The accurate analysis of the seismic response of isolated structures requires incorporation of the flexibility of supporting soil. However, it is often customary to idealize the soil as rigid during the analysis of such structures. In this paper, seismic response time history analyses of base-isolated buildings modelled as linear single degree-of-freedom (SDOF) and multi degree-of-freedom (MDOF) systems with linear and nonlinear base models considering and ignoring the flexibility of supporting soil are conducted. The flexibility of supporting soil is modelled through a lumped parameter model consisting of swaying and rocking spring-dashpots. In the analysis, a large number of parametric studies for different earthquake excitations with three different peak ground acceleration (PGA) levels, different natural periods of the building models, and different shear wave velocities in the soil are considered. For the isolation system, laminated rubber bearings (LRBs) as well as high damping rubber bearings (HDRBs) are used. Responses of the isolated buildings with and without SSI are compared under different ground motions leading to the following conclusions: (1) soil flexibility may considerably influence the stiff superstructure response and may only slightly influence the response of the flexible structures; (2) the use of HDRBs for the isolation system induces higher structural peak responses with SSI compared to the system with LRBs; (3) although the peak response is affected by the incorporation of soil flexibility, it appears insensitive to the variation of shear wave velocity in the soil; (4) the response amplifications of the SDOF system become closer to unit with the increase in the natural period of the building, indicating an inverse relationship between SSI effects and natural periods for all the considered ground motions, base isolations and shear wave velocities; (5) the incorporation of SSI increases the number of significant cycles of large amplitude accelerations for all the stories, especially for earthquakes with low and moderate PGA levels; and (6) buildings with a linear LRB base-isolation system exhibit larger differences in displacement and acceleration amplifications, especially at the level of the lower stories.
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| 4. |
- Makatini, Maya M., et al.
(författare)
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Pentacycloundecane-based inhibitors of wild-type C-South African HIV-protease
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:8, s. 2274-2277
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we present the first account of pentacycloundecane (PCU) peptide based HIV-protease inhibitors. The inhibitor exhibiting the highest activity made use of a natural HIV-protease substrate peptide sequence, that is, attached to the cage (PCU-EAIS). This compound showed nanomolar IC50 activity against the resistance-prone wild type C-South African HIV-protease (C-SA) catalytic site via a norstatine type functional group of the PCU hydroxy lactam. NMR was employed to determine a logical correlation between the inhibitory concentration (IC50) results and the 3D structure of the corresponding inhibitors in solution. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. The results from docking experiments coincided with the experimental observed activities. These findings open up useful applications for this family of cage peptide inhibitors, considering the vast number of alternative disease related proteases that exist.
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| 5. |
- Makatini, Maya M., et al.
(författare)
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Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors
- 2013
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Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Informa UK Limited. - 1475-6366 .- 1475-6374. ; 28:1, s. 78-88
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Tidskriftsartikel (refereegranskat)abstract
- In this study, eight non-natural peptides and peptoids incorporating the pentacycloundecane (PCU) lactam were designed and synthesized as potential inhibitors of the wild type C-SA HIV-protease. Five of these inhibitors gave IC50 values ranging from 0.5 up to 0.75 mu M against the resistance-prone wild type C-South African HIV-protease. NMR EASY-ROESY studies enabled us to describe the secondary structure of three of these compounds in solution. The 3D structures of the selected cage peptides were also modelled in solution using QM/MM/MD simulations. Satisfactory agreement between the NMR observations and the low energy calculated structures exists. Only one of these inhibitors (11 peptoid), which showed the best IC50 (0.5 mu M), exhibited a definable 3-D structure in solution. Autodock4 and AutodockVina were used to model the potential interaction between these inhibitors and the HIV-PR. It appears that the docking results are too crude to be correlated with the relative narrow range of experimental IC50 values (0.5-10 mu M). The PCU-peptides and peptoides were several orders less toxic (145 mu M for 11 and 102 mu M for 11 peptoid) to human MT-4 cells than lopinavir (0.025 mu M). This is the first example of a polycyclic cage framework to be employed as an HIV-PR transition state analogue inhibitor and can potentially be utilized for other diseases related proteases.
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| 6. |
- Makatini, Maya M., et al.
(författare)
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Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors : A hybrid 2D NMR and docking/QM/MM/MD approach
- 2011
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 46:9, s. 3976-3985
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Tidskriftsartikel (refereegranskat)abstract
- Pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors were synthesized and nanomolar activity against the resistance-prone wild type C-South African HIV protease is reported. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. EASY-ROESY NMR experiments gave information about the 3D structure of the cage peptides and 3D solution structure could be linked to the experimental IC(50) activity profile of the considered inhibitors. QM/MM/MD simulations of the inhibitors in solution confirmed the NMR observed conformations. Docking experiments and QM/MM/MD simulations of the inhibitor-HIV PR complexes were also performed. These computational results complimented the experimental inhibition activities and enabled us to report a unique binding mode for PCU-based inhibitors at the active site of HIV-protease enzyme. A conserved hydrogen bonding pattern between the norstatine type functional group of the PCU hydroxylactam and active site residues, ASP25/ASP25', was observed in all active compounds. The biological significance and possible mode of inhibition by PCU-based HIV PR inhibitors discussed herein provide us with a deeper understanding of the mode of action of these novel inhibitors. The PCU-peptides are between 6000 and 8500 time less toxic to human MT-4 cells than Lopinavir. This potentially creates new application avenues for these putative inhibitors to be investigated against a vast number of other disease-related proteases.
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| 7. |
- Makatini, Maya M., et al.
(författare)
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Synthesis, screening and computational investigation of pentacycloundecane-peptoids as potent CSA-HIV PR inhibitors
- 2012
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 57, s. 459-467
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Tidskriftsartikel (refereegranskat)abstract
- Herein, we present the first pentacycloundecane (PCU) diol peptoid derived HIV protease inhibitors with IC50 values ranging from 6.5 to 0.075 mu M. Five derivatives were synthesized in an attempt to understand the structure activity relationship of this class of compounds for HIV protease inhibition. NMR spectroscopy (new Efficient Adiabatic Symmetrized Rotating Overhauser Effect Spectroscopy, EASY-ROESY) was employed to determine the predominant conformation of the active compound. In this study docking studies and MD simulations provided insight into the binding theme of this class of peptoid inhibitors to the CSA-HIV PR active site. Conserved and stable hydrogen bonding between the hydroxyl groups of the inhibitors and the active site Asp25/Asp25' residues were observed from the docking and along the MD trajectories.
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