Medicinal chemistry articles within Nature Communications

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  • Article
    | Open Access

    Polyketide macrolides are of interest for drug discovery but their inherent structural and stereochemical complexity hinders the exploration of related regions of chemical space more broadly. Here, the authors designed in silico and synthesized a library of tetrahydrofuran-containing polyketide macrolides, and screened them against a panel of biological assays, identifying biologically active library members.

    • Darryl M. Wilson
    • , Daniel J. Driedger
    •  & Robert A. Britton
  • Article
    | Open Access

    Antimicrobial resistance is a global health threat and the development of alternative strategies to overcome it is of high interest. Here, the authors report proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery, and apply them for targeting a range of mycobacterial strains, including antibiotic-resistant ones.

    • Lukas Junk
    • , Volker M. Schmiedel
    •  & Guido Boehmelt
  • Article
    | Open Access

    GPR34 is a GPCR which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative endogenous ligand. Here, authors report two cryo-EM structures of human GPR34-Gi complex with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or its derivative M1.

    • Tamaki Izume
    • , Ryo Kawahara
    •  & Osamu Nureki
  • Article
    | Open Access

    Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects but total synthesis procedures are often limited by the scale. Here, the authors present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol.

    • Peihao Chen
    • , Jing Wang
    •  & Xiangbing Qi
  • Article
    | Open Access

    Regioselectivity prediction for many reactions remains a challenging target for a priori prediction. Here, the authors develop a machine learning model that predicts the outcomes of Minisci reactions.

    • Emma King-Smith
    • , Felix A. Faber
    •  & Alpha A. Lee
  • Article
    | Open Access

    Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.

    • Arun Chandramohan
    • , Hubert Josien
    •  & Anthony W. Partridge
  • Article
    | Open Access

    Avapritinib, a potent inhibitor, offers hope for D842V-mutant GIST patients with high response rates; however, resistance and side effects remain challenges. Here, crystal structures shed light on this and reveal a Gα-pocket for drug development.

    • A. Teuber
    • , T. Schulz
    •  & D. Rauh
  • Article
    | Open Access

    Targeted protein degradation (TPD) is an emerging therapeutic that can lead to proteasomal degradation of target proteins. Here, the authors combine nano-scale, automated synthesis and cell-based, direct-to-biology screening, allowing them to discover and profile Molecular Glues (MGs) degrading substrates via the Cereblon E3 ubiquitin ligase.

    • Zefeng Wang
    • , Shabnam Shaabani
    •  & Alexander Dömling
  • Article
    | Open Access

    Serotonin 5-HT2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT2A-selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT2A-Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.

    • Jason Wallach
    • , Andrew B. Cao
    •  & John D. McCorvy
  • Article
    | Open Access

    Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions, but most of the photocleavable groups cannot be directly activated by near-infrared (NIR) light that features deep penetration and low phototoxicity. Here, the authors report an upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis.

    • Kaiqi Long
    • , Wen Lv
    •  & Weiping Wang
  • Article
    | Open Access

    Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence.

    • Ming Jiang
    • , Mirjam C. W. Huizenga
    •  & Mario van der Stelt
  • Article
    | Open Access

    Targeted protein degradation (TPD) has emerged as a new paradigm for modulating protein activity. Here, the authors develop bifunctional degraders combining a putative ligand of the autophagy-related LC3 protein with different protein targets, which direct proteins of interest to the proteasome by covalently targeting the DCAF11 E3 ligase substrate receptor.

    • Gang Xue
    • , Jianing Xie
    •  & Herbert Waldmann
  • Article
    | Open Access

    While carbon-introducing difunctionalization of C-C double bonds is well established, the analogous difunctionalization for introducing germanium group and other functionalities remains elusive. Here, the authors describe a nickel-catalyzed germylative alkylation of activated olefins with easily accessible primary, secondary and tertiary alkyl bromides and chlorogermanes as the electrophiles to form C-Ge and C-Calkyl bonds simultaneously.

    • Rui Gu
    • , Xiujuan Feng
    •  & Xuan Zhang
  • Article
    | Open Access

    Traditional metallaphotocatalysis often requires two or more separate catalysts and is considered to be costly and not tolerant towards a wide substrate scope. Here the authors realize metallaphotocatalysis with a bifunctional dirhodium tetracarboxylate as single catalyst component to merge carbenoid chemistry and 1O2 chemistry.

    • Taoda Shi
    • , Tianyuan Zhang
    •  & Wenhao Hu
  • Article
    | Open Access

    Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. Here, the authors develop a potent activator ZK53 that is highly selective on human ClpP but inactive toward bacterial ClpP proteins, and show that ZK53 causes cell cycle arrest via ClpP on lung squamous cell carcinoma cells and exhibits therapeutic effects in animal models.

    • Lin-Lin Zhou
    • , Tao Zhang
    •  & Cai-Guang Yang
  • Comment
    | Open Access

    Machine learning is a powerful tool for the study and design of molecules. Here the authors comment a recent publication in Nature Communications which highlights the challenges of different molecular representations for data-driven property predictions.

    • Ana Laura Dias
    • , Latimah Bustillo
    •  & Tiago Rodrigues
  • Article
    | Open Access

    AI has become a crucial tool for drug discovery, but how to properly represent molecules for data-driven property prediction is still an open question. Here the authors evaluate 62,820 models to highlight existing challenges, the impact of activity cliffs, and the crucial role of dataset size.

    • Jianyuan Deng
    • , Zhibo Yang
    •  & Fusheng Wang
  • Article
    | Open Access

    Designing novel molecules with desired bioactivity is a critical challenge in drug discovery, particularly for novel or understudied targets. The authors propose a pharmacophore-guided deep learning approach PGMG to generate diverse active-like molecules with limited activity data.

    • Huimin Zhu
    • , Renyi Zhou
    •  & Min Li
  • Article
    | Open Access

    The phenyl ring is a basic structural element in chemistry. Here, the authors show the design, synthesis, and validation of 2-oxabicyclo[2.2.2]octane as a new saturated bioisostere with improved physicochemical properties

    • Vadym V. Levterov
    • , Yaroslav Panasiuk
    •  & Pavel K. Mykhailiuk
  • Article
    | Open Access

    Solvent shielding of the amide hydrogen bond donor through chemical modification or conformational control has been successfully utilized to impart membrane permeability to macrocyclic peptides. Here, the authors show that passive membrane permeability can also be conferred by masking the amide hydrogen bond acceptor through thioamide substitution, leading to improved pharmacological properties of peptide macrocycles.

    • Pritha Ghosh
    • , Nishant Raj
    •  & Jayanta Chatterjee
  • Article
    | Open Access

    The Mannich reaction is a well-established method for the synthesis of β-amino carbonyl compounds while the analogous reactions of homo-enol or its equivalents with imines or iminium ions are much less explored. Here, the authors describe a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction.

    • Hanyue Qiu
    • , Xinghai Fei
    •  & Min Zhang
  • Article
    | Open Access

    While a variety of well-established methods enable the control of a stereogenic center, a catalytic method for controlling a stereogenic axis in one substrate is typically unavailable for controlling axial chirality in other substrates with a similar structure. Here, the authors report o-amidobiaryl as a flexible platform for chiral phosphoric acid catalyzed atroposelective dynamic kinetic resolution.

    • Ahreum Kim
    • , Chanhee Lee
    •  & Yongseok Kwon
  • Article
    | Open Access

    The lack of efficient and diverse synthesis strategy has hindered the study of perifused cycles. Here, the authors report a metal-catalyzed cascade electrocyclization to access 5,6,7-perifused cycles, and demonstrated the versatility of this protocol in the late-stage modification of pharmaceuticals.

    • Jingpeng Han
    • , Yongjian Yang
    •  & Baosheng Li
  • Article
    | Open Access

    Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Here, the authors report crystal structures of HSD17B13 and its complexes with two series of inhibitors.

    • Shenping Liu
    • , Ruth F. Sommese
    •  & Michelle F. Clasquin
  • Article
    | Open Access

    Most DNA-encoded library (DEL) syntheses are limited by the presence of sensitive DNA-based constructs. Here, the authors develop DOSEDO, a diverse 3.7 million compound DEL, generated through diversity-oriented synthesis that provides enhanced scaffold and exit vector diversity and gives validated binding hits for multiple protein targets.

    • Liam Hudson
    • , Jeremy W. Mason
    •  & Karin Briner
  • Article
    | Open Access

    Branched chain ketoacid dehydrogenase kinase (BDK) inhibits the activity of branched chain ketoacid dehydrogenase and branched chain amino acid degradation, implicated in several diseases. Here, the authors discover a BDK inhibitor and degrader that shows efficacy in rodent metabolism and heart failure models, as well as another class of BDK inhibitors that stabilizes BDK.

    • Rachel J. Roth Flach
    • , Eliza Bollinger
    •  & Kevin J. Filipski
  • Article
    | Open Access

    The lack of a universal platform for PROTAC development remains a major bottleneck. Here, the authors report modular DNA framework-based PROTACs (DbTACs) that enable precise control of the linker length and selective degradation of diverse targets in different cellular compartments using various warheads.

    • Li Zhou
    • , Bin Yu
    •  & Yi Ma
  • Article
    | Open Access

    High-throughput experimentation is an increasingly important tool in reaction discovery, while there remains a need for software solutions to navigate data-rich experiments. Here the authors report phactor™, a software that facilitates the performance and analysis of high-throughput experimentation in a chemical laboratory.

    • Babak Mahjour
    • , Rui Zhang
    •  & Tim Cernak
  • Review Article
    | Open Access

    Positron emission tomography is widely used to diagnose and monitor different disease states and interest in the technique has led to the demand for the development of new method for radiolabelling. Here the authors review the recent progress in the development of new PET probes.

    • Jian Rong
    • , Ahmed Haider
    •  & Steven H. Liang
  • Article
    | Open Access

    Despite the therapeutic interest in targeting CDK2, developing a selective CDK2 inhibitor has been challenging. Here, the authors describe a potent and selective CDK2 inhibitor that binds an allosteric pocket, preventing activating protein partners from binding and showing potential as a contraceptive.

    • Erik B. Faber
    • , Luxin Sun
    •  & Gunda I. Georg
  • Article
    | Open Access

    Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for antiproliferative therapies for cancers where it is essential. Here, the authors develop a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations.

    • Magali Saez-Ayala
    • , Laurent Hoffer
    •  & Xavier Morelli