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Salvador Guardiola Monica Varese Xavier Roig Macarena Snchez-Navarro Jesús García Ernest Giralt 《Chemical science》2021,12(14):5164
Peptides are a rapidly growing class of therapeutics with various advantages over traditional small molecules, especially for targeting difficult protein–protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing bioactive cyclic topologies that go beyond natural l-amino acids. Here, we report a generalizable framework that exploits the computational power of Rosetta, in terms of large-scale backbone sampling, side-chain composition and energy scoring, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we developed two new inhibitors (PD-i3 and PD-i6) of programmed cell death 1 (PD-1), a key immune checkpoint in oncology. A comprehensive biophysical evaluation was performed to assess their binding to PD-1 as well as their blocking effect on the endogenous PD-1/PD-L1 interaction. Finally, NMR elucidation of their in-solution structures confirmed our de novo design approach. In silico design of heterochiral cyclic peptides that bind to a specific surface patch on the target protein (PD-1, in this case) and disrupt protein–protein interactions. 相似文献
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César Ruiz-Zambrana Rajeev K. Dubey Macarena Poyatos Prof. Aurelio Mateo-Alonso Prof. Eduardo Peris 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(44):e202201384
A series of rhodium and iridium complexes with a N-heterocyclic carbene (NHC) ligand decorated with a perylene-diimide-pyrene moiety are described. Electrochemical studies reveal that the complexes can undergo two successive one-electron reduction events, associated to the reduction of the PDI moiety attached to the NHC ligand. The reduction of the ligand produces a significant increase on its electron-donating character, as observed from the infrared spectroelectrochemical studies. The rhodium complex was tested in the [3+2] cycloaddition of diphenylcyclopropenone and methylphenylacetylene, where it displayed a redox-switchable behavior. The neutral complex showed moderate activity, which was suppressed when the catalyst was reduced. 相似文献
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Versatile Iridicycle Catalysts for Highly Efficient and Chemoselective Transfer Hydrogenation of Carbonyl Compounds in Water 下载免费PDF全文
Dinesh Talwar Dr. Xiaofeng Wu Dr. Ourida Saidi Noemí Poyatos Salguero Prof. Jianliang Xiao 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(40):12835-12842
Cyclometalated iridium complexes are shown to be highly efficient and chemoselective catalysts for the transfer hydrogenation of a wide range of carbonyl groups with formic acid in water. Examples include α‐substituted ketones (α‐ether, α‐halo, α‐hydroxy, α‐amino, α‐nitrile or α‐ester), α‐keto esters, β‐keto esters and α,β‐unsaturated aldehydes. The reduction was carried out at substrate/catalyst ratios of up to 50 000 at pH 4.5 and required no organic solvent. The protocol provides a practical, easy and efficient way for the synthesis of β‐functionalised secondary alcohols, such as β‐hydroxyethers, β‐hydroxyamines and β‐hydroxyhalo compounds, which are valuable intermediates in pharmaceutical, fine chemical, perfume and agrochemical synthesis. 相似文献
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Carlos Obreque Macarena Donoso Gabriel Gutiérrez Vladimir Marianov 《European Journal of Operational Research》2010
The Hierarchical Network Design Problem consists of locating a minimum cost bi-level network on a graph. The higher level sub-network is a path visiting two or more nodes. The lower level sub-network is a forest connecting the remaining nodes to the path. We optimally solve the problem using an ad hoc branch and cut procedure. Relaxed versions of a base model are solved using an optimization package and, if binary variables have fractional values or if some of the relaxed constraints are violated in the solution, cutting planes are added. Once no more cuts can be added, branch and bound is used. The method for finding valid cutting planes is presented. Finally, we use different available test instances to compare the procedure with the best known published optimal procedure, with good results. In none of the instances we needed to apply branch and bound, but only the cutting planes. 相似文献
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CáRDENAS Carlos MU?OZ Macarena CONTRERAS Julia AYERS Paul W. GóMEZ Tatiana FUENTEALBA Patricio 《物理化学学报》2018,34(6):631-638
Chemical reactivity towards electron transfer is captured by the Fukui function.However,this is not well defined when the system or its ions have degenerate or pseudo-degenerate ground states.In such a case,the first-order chemical response is not independent of the perturbation and the correct response has to be computed using the mathematical formalism of perturbation theory for degenerate states.Spatialpseudo-degeneracy is ubiquitous in nanostructures with high symmetry and totally extended systems.Given the size of these systems,using degenerate-state perturbation theory is impractical because it requires the calculation of many excited states.Here we present an alternative to compute the chemical response of extended systems using models of local softness in terms of the local density of states.The local softness is approximately equal to the density of states at the Fermi level.However,such approximation leaves out the contribution of inner states.In order to include and weight the contribution of the states around the Fermi level,a model inspired by the long-range behavior of the local softness is presented.Single wall capped carbon nanotubes(SWCCNT) illustrate the limitation of the frontier orbital theory in extended systems.Thus,we have used a C360 SWCCNT to test the proposed model and how it compares with available models based on the local density of states.Interestingly,a simple Hü ckel approximation captures the main features of chemical response of these systems.Our results suggest that density-of-states models of the softness along simple tight binding Hamiltonians could be used to explore the chemical reactivity of more complex system,such a surfaces and nanoparticles. 相似文献