Article
Pharmacology & Pharmacy
Teresa Minguez-Vinas, Beatriz E. Nielsen, Deborah K. Shoemark, Cecilia Gotti, Richard B. Sessions, Adrian J. Mulholland, Cecilia Bouzat, Susan Wonnacott, Timothy Gallagher, Isabel Bermudez, Ana Sofia Oliveira
Summary: The alpha 7 and alpha 4 beta 2* nicotinic acetylcholine receptors are the most abundant nAChRs in the mammalian brain and are targeted in drug discovery for brain disorders. A C(10) variant of cytisine has been developed as a partial agonist of alpha 4 beta 2 nAChR. Molecular dynamic simulations and experiments revealed the structural basis for the selectivity of 10-methylcytisine for alpha 7 and alpha 4 beta 2 nAChRs, providing insights into agonist binding and receptor dynamics.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Chemistry, Physical
Claire Empel, Sripati Jana, Adithyaraj Koodan, Rene M. Koenigs
Summary: In this study, a photocatalytic orthoalkylation reaction was reported, which achieved the reaction between 2-phenyl pyridines and N-protected maleimides using a catalyst and an additive at room temperature. Experimental and theoretical studies revealed a reaction mechanism that involved both dark and light reactions, with the photochemical excitation facilitating the ligand exchange and protodemetalation reaction.
Article
Multidisciplinary Sciences
Shi Cao, Wei Hong, Ziqi Ye, Lei Gong
Summary: The study demonstrates the use of a dual asymmetric photocatalyst leading to the development of asymmetric sulfonylation involving direct functionalization of cycloalkanes, alkanes, toluene derivatives or ethers.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Shiyan Cheng, Qianyu Li, Xiuliang Cheng, Yu-Mei Lin, Lei Gong
Summary: This review summarizes recent progress in asymmetric reactions of alkanes and cycloalkanes, focusing on the generation of stereocenters and stereogenic centers. Elegant catalytic strategies are discussed, which enable selective recognition of C-H bonds at specific positions while maintaining high levels of stereoselectivity.
CHINESE JOURNAL OF CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Qing-Feng Xu-Xu, Yuji Nishii, Yuta Uetake, Hidehiro Sakurai, Masahiro Miura
Summary: A rhodium-catalyzed direct selenium annulation using stable elemental selenium was introduced in this manuscript, leading to the successful synthesis of a series of isoselenazolones. A new selenation mechanism involving a highly electrophilic Se(IV) species as the reactive selenium donor was proposed and further verified by computational study.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Chemistry, Organic
Jianxiao Li, Dan He, Bowen Wang, Wenfang Xiong, Chaorong Qi, Huanfeng Jiang
Summary: In this paper, a novel and versatile reaction method for the synthesis of alkyl substituted alpha-methylene-gamma-lactones from unactivated alkenes has been reported. This reaction is enabled by Lewis acids and palladium catalysts, and exhibits high yields and excellent Z/E selectivities. The downstream functionalization of (Z)-gamma-lactones allows for the preparation of various valuable complex molecules, and has potential utility in organic synthesis and pharmaceutical chemistry.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Chemistry, Organic
Xiang Zhao, Xuelin Yue, Zeng Han, Yadong Feng, Ting Gao, Sanshu Li, Xiuling Cui
Summary: An efficient method for the synthesis of 6-alkenylindazolo[3,2-a]isoquinolines via rhodium(iii)-catalysed C-H bond activation/subsequent [4 + 2] cyclization has been developed. The obtained products exhibited excellent regioselectivity and fluorescence properties, making them suitable for DNA staining and labeling of zebrafish larvae yolk.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Chemistry, Organic
Xiao-Wen Wang, Rui-Xue Li, Yang Deng, Ming-Qiu-Hao Fu, Ya-Nan Zhao, Zhi Guan, Yan-Hong He
Summary: This article proposes a new method for the direct hydroxylarylation of unactivated benzylic carbons (sp3/sp2/sp) without the need for pre-functionalized benzylic alcohols, aromatic aldehydes, or ketones. It features direct functionalization of unactivated benzylic C(sp3)-H bonds and benzylic sp2/sp-carbons, mild conditions (open air, room temperature), an environmentally friendly procedure (without any external catalyst/mediator/additive), and direct access to sterically hindered alcohols from inexpensive and readily available alkyl/alkenyl/alkynylbenzenes. Mechanistic studies strongly support the proposed radical-radical cross-coupling between transient ketyl radicals and persistent radical anions. Gram-scale synthesis and diversification of drug derivatives demonstrate the practical potential of this protocol.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Alvaro Velasco-Rubio, Pol Martinez-Balart, Andres M. Alvarez-Constantino, Martin Fananas-Mastral
Summary: Direct functionalization of alkanes is a significant challenge in developing efficient and clean C-C bond forming reactions due to the low reactivity of aliphatic C-H bonds. Photocatalytic processes using hydrogen atom transfer C-H bond activation strategies have emerged as useful tools to activate and functionalize these inert compounds. This article summarizes the main achievements in this field for developing C-C bond forming reactions and discusses the key mechanistic features enabling these transformations.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Organic
Guanghua Kuang, Dandan Liu, Xuerong Chen, Guangyuan Liu, Yang Fu, Yiyuan Peng, Hua Li, Yirong Zhou
Summary: A unified method for direct C4-H halogenation of indoles has been successfully achieved with the assistance of anthranilic acids as suitable transient directing groups. Exclusive site selectivity and good functional group tolerance were obtained using inexpensive N-halosuccinimides as halogen sources under mild conditions. The rich functional groups in the product allow for facile construction of a diversity of nitrogen-containing heterocycles via one-step late-stage derivations.
Article
Chemistry, Applied
Shanping Chen, Kai Hu, Wei Feng, Guojiang Mao, Yuxia Li, Guo-Jun Deng
Summary: A direct strategy for the synthesis of fused thienoindoles from substituted indoles and elemental sulfur has been reported. This method yields a range of structurally valuable fused thienoindoles in 51-78% yield under transition-metal-free conditions, potentially useful in pharmaceutical industry and organic functional materials.
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Article
Chemistry, Organic
Bholanath Garai, Molla Rahamat Ali, Rajib Mandal, Basker Sundararaju
Summary: This study demonstrates the C(8)-selective nucleophilic cascade cyclization of quinoline N-oxide with easily derived 1,6-enyne from phenol derivatives. Various quinoline N-oxide and alkynes are suitable for producing a library of quinoline N-oxide tethered cishydrobenzofurans with high yields and excellent functional group tolerance. The protocol's utility is achieved through post-synthetic modification of the cyclized product. Mechanistic studies suggest a base-assisted internal electrophilic-type substitution (BIES)-type pathway for C-H bond activation, and electrospray ionization mass spectrometry (ESI-MS) analysis confirms the formation of a key five-membered cobaltacycle.
Article
Chemistry, Organic
Bholanath Garai, Molla Rahamat Ali, Rajib Mandal, Basker Sundararaju
Summary: This study demonstrates the C(8)-selective nucleophilic cascade cyclization of quinoline N-oxide with easily derived 1,6-enyne from phenol derivatives. Various quinoline N-oxide and alkynes are found to be suitable for producing a library of quinoline N-oxide tethered cis-hydrobenzofurans with high yields and excellent functional group tolerance. The utility of the protocol has been achieved through post-synthetic modification of the cyclized product. Mechanistic studies reveal a base-assisted internal electrophilic-type substitution (BIES)-type pathway for C-H bond activation, and electrospray ionization mass spectrometry (ESI-MS) analysis confirms the formation of a key five-membered cobaltacycle.
Article
Chemistry, Physical
Daniele Antermite, Andrew J. P. White, Luis Casarrubios, James A. Bull
Summary: This study presents a combined experimental and computational investigation on the regio- and stereoselective C4 arylation of pyrrolidines and piperidines using C3 aminoquinoline amide directing groups. The mechanistic experiments reveal a cis-selective pathway and the discovery of an improved directing group. This study contributes to the understanding and improvement of C-H functionalization of N-heterocycles.
Article
Chemistry, Multidisciplinary
Masahiro Abe, Yuka Yokoi, Aoi Hirata, Yumeno Matsuoka, Tetsutaro Kimachi, Kiyofumi Inamoto
Summary: The direct and selective functionalization of inert C-H bonds through intramolecular hydrogen atom transfer (HAT) is a powerful tool in organic synthesis. In this study, we designed an efficient and facile method for iodine atom transfer in fluorinated alkyl iodides via 1,5-HAT reaction. Our process allows for site-selective iodination with good yields, producing di- and tri-fluorinated alkyl iodides. Additionally, our method demonstrates excellent atom economy and high tolerance towards various functional groups.
CHEMICAL COMMUNICATIONS
(2022)
Article
Computer Science, Hardware & Architecture
Abigail Dommer, Lorenzo Casalino, Fiona Kearns, Mia Rosenfeld, Nicholas Wauer, Surl-Hee Ahn, John Russo, Sofia Oliveira, Clare Morris, Anthony Bogetti, Anda Trifan, Alexander Brace, Terra Sztain, Austin Clyde, Heng Ma, Chakra Chennubhotla, Hyungro Lee, Matteo Turilli, Syma Khalid, Teresa Tamayo-Mendoza, Matthew Welborn, Anders Christensen, Daniel Ga Smith, Zhuoran Qiao, Sai K. Sirumalla, Michael O'Connor, Frederick Manby, Anima Anandkumar, David Hardy, James Phillips, Abraham Stern, Josh Romero, David Clark, Mitchell Dorrell, Tom Maiden, Lei Huang, John McCalpin, Christopher Woods, Alan Gray, Matt Williams, Bryan Barker, Harinda Rajapaksha, Richard Pitts, Tom Gibbs, John Stone, Daniel M. Zuckerman, Adrian J. Mulholland, Thomas Miller, Shantenu Jha, Arvind Ramanathan, Lillian Chong, Rommie E. Amaro
Summary: This study aims to completely revise the current models of airborne transmission of SARS-CoV-2 virus by providing atomic-level views of the virus within respiratory aerosols. It extends the capabilities of multiscale computational microscopy to address the limitations of current experimental methods in interrogating aerosols at the atomic/molecular level. The study presents initial scientific discoveries for the SARS-CoV-2 Delta variant, highlighting the potential scientific impact of the work.
INTERNATIONAL JOURNAL OF HIGH PERFORMANCE COMPUTING APPLICATIONS
(2023)
Article
Pharmacology & Pharmacy
Nokomis Ramos-Gonzalez, Sam Groom, Katy J. Sutcliffe, Sukhvinder Bancroft, Chris P. Bailey, Richard B. Sessions, Graeme Henderson, Eamonn Kelly
Summary: The illicit use of fentanyl-like drugs and the resulting overdose deaths is a major problem. This study compared the efficacy and signaling bias of different fentanyls, and found that carfentanil is biased towards beta-arrestin.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Cell Biology
Natalia Jimenez-Moreno, Madhu Kollareddy, Petros Stathakos, Joanna J. Moss, Zurine Anton, Deborah K. Shoemark, Richard B. Sessions, Ralph Witzgall, Maeve Caldwell, Jon D. Lane
Summary: LMX1A and LMX1B are essential for dopaminergic neuronal differentiation and survival, and they also act as transcription factors for cellular stress protection through autophagy. Their suppression impairs autophagy response and mitochondrial function, while their inducible overexpression protects against rotenone toxicity in vitro.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Chonnikan Hanpaibool, Natharin Ngamwongsatit, Puey Ounjai, Sirilata Yotphan, Peter Wolschann, Adrian J. Mulholland, James Spencer, Thanyada Rungrotmongkol
Summary: The last line antibiotic colistin is effective against extensively resistant Gram-negative bacteria. Resistance to colistin occurs through the catalyzing of phosphoethanolamine (PEA) transfer onto lipid A by the mobile colistin resistance (mcr) gene family. Molecular dynamics simulations show structural differences in the active sites of MCR-1 and MCR-3, which may explain differential effects of pyrazolones on producer E. coli.
Article
Chemistry, Multidisciplinary
H. T. Henry Chan, A. Sofia F. Oliveira, Christopher J. Schofield, Adrian J. Mulholland, Fernanda Duarte
Summary: The SARS-CoV-2 main protease (M-pro) is crucial in the coronavirus lifecycle by breaking down viral polyproteins. This study used dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to examine the behavior of M-pro with and without substrates. The results reveal communication between M-pro subunits and identify networks associated with allosteric inhibition and nirmatrelvir resistance. These findings suggest that certain mutations can lead to drug resistance by altering the allosteric behavior of M-pro. Overall, the study demonstrates the usefulness of D-NEMD in identifying functionally relevant allosteric sites and networks, including those relevant to drug resistance.
Article
Neurosciences
Teresa Minguez-Vinas, Varsha Prakash, Kaiqian Wang, Sarah H. Lindstrom, Serena Pozzi, Stuart A. Scott, Elizabeth Spiteri, David A. Stevenson, Euan A. Ashley, Cecilia Gunnarsson, Antonios Pantazis
Summary: Two variants of the KCNA2 gene were found in pediatric patients with epilepsy and developmental delay. These variants had opposite effects on neuronal excitability, with one variant increasing surface trafficking and activity of the channel, and the other variant reducing surface levels and inhibiting channel opening.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Multidisciplinary Sciences
George H. Hutchins, Claire E. M. Noble, H. Adrian Bunzel, Christopher Williams, Paulina Dubiel, Sathish K. N. Yadav, Paul M. Molinaro, Rob Barringer, Hector Blackburn, Benjamin J. Hardy, Alice E. Parnell, Charles Landau, Paul R. Race, Thomas A. A. Oliver, Ronald L. Koder, Matthew P. Crump, Christiane Schaffitzel, A. Sofia F. Oliveira, Adrian J. Mulholland, J. L. Ross Anderson
Summary: The electron-conducting circuitry of life is a valuable, yet untapped resource in nanoscale biomolecular engineering. Researchers have characterized and analyzed a new diheme maquette protein, 4D2, and used it to create a modular platform for heme protein design. They redesigned a monoheme variant and validated its properties through experimental electrostatic redox potential calculations. 4D2 was then extended into a tetraheme helical bundle, demonstrating its potential as a molecular wire. This platform presents opportunities for redox protein design and the development of artificial electron-conducting circuitry in the future.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Letter
Chemistry, Physical
Abbie Lear, J. L. Ross Anderson, Donald Hilvert, Vickery L. Arcus, Marc W. van der Kamp, H. Adrian Bunzel, Adrian J. Mulholland
Summary: Activation heat capacity is an important factor in enzyme evolution and thermoadaptation. We found that the emergence of curved activity-temperature profiles in a designer enzyme was due to the selective rigidification of its transition state ensemble that induced an activation heat capacity. However, simulations by angstrom qvist challenged our findings, suggesting that the experimental observations were caused by a change in the rate-limiting step.
Correction
Multidisciplinary Sciences
Leonor Guerra-Guimaraes, Carla Pinheiro, Ana Sofia F. Oliveira, Andrea Mira-Jover, Javier Valverde, Fernanda A. de F. Guedes, Herlander Azevedo, Vitor Varzea, Antonio Jesus Munoz Pajares
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Helen M. Deeks, Kirill Zinovjev, Jonathan Barnoud, Adrian J. Mulholland, Marc W. van der Kamp, David R. Glowacki
Summary: This study proposes a two-step approach that combines interactive molecular dynamics in virtual reality with free energy calculation to explore biological processes at the molecular level. The method generates diverse protein-ligand unbinding pathways using a human-in-the-loop iMD-VR framework and calculates the corresponding free energy profiles using FE methods. The approach offers an intuitive way for researchers to qualitatively and quantitatively investigate candidate pathways in biomolecular systems.
SCIENTIFIC REPORTS
(2023)
Article
Cell Biology
A. Sofia F. Oliveira, Deborah K. Shoemark, Andrew D. Davidson, Imre Berger, Christiane Schaffitzel, Adrian J. Mulholland
Summary: The spike protein of SARS-CoV-2 contains a fatty acid binding site that is functionally important. Removing the fatty acid can significantly affect the conformation and functionality of the spike protein. Different variants of SARS-CoV-2 have varying responses to the removal of the fatty acid, indicating potential differences in transmissibility and virulence. Experimental comparison of the effects of the fatty acid on different variants is necessary.
JOURNAL OF MOLECULAR CELL BIOLOGY
(2023)
Article
Biochemical Research Methods
Joe Crossley-Lewis, Josh Dunn, Corneliu Buda, Glenn J. Sunley, Alin M. Elena, Ilian T. Todorov, Chin W. Yong, David R. Glowacki, Adrian J. Mulholland, Neil L. Allan
Summary: Interactive molecular dynamics simulation in virtual reality (iMD-VR) is a promising technique in molecular science, with applications in materials science and heterogeneous catalysis. This study demonstrates the use of iMD-VR in investigating lithium fast ion conduction mechanisms and exploring diffusion within zeolites.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2023)
