Medicinal chemistry articles within Nature Communications

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.

Attempts to explain molecular property predictions of neural networks are not always compatible with chemical intuition based on chemical substructures. Here the authors propose the substructure mask explanation method to tackle this challenge.

Efficient screening of protein-drug interactions (PDIs) has been impeded by the limitations of current biophysical approaches. Here, the authors present a funneled YaxAB nanopore sensor which allows label-free, single-molecule detection of proteins and PDIs.

The development of direct-acting antivirals to combat COVID-19 remains an important goal. Here the authors design covalent inhibitors that target the papain-like protease from SARS-CoV-2. The most promising inhibitor blocks viral replication in mammalian cells.

Engineering excitation wavelength of photosensitizers allows to enhanced reactive oxygen species but controlling the wavelength corresponding to operating conditions remains challenging. Here, the authors implement a wavelength-engineerable imidazolium-based porous organic polymer and demonstrate tuning of the optimal wavelength for maximum performance by modifying the linker system.

Naturally occurring peptides with high membrane permeability often have backbone ester bonds. Here, the authors investigated the effect of an amide-to-ester substitution on membrane permeability of peptides and found the substitution is useful for improving membrane permeability of cyclic peptides.

Dual-pharmacophore DNA-Encoded Libraries (DELs) can generate large libraries, but linker optimisation is challenging. Here, the authors report a trio-pharmacophore DEL (T-DEL) for both de novo fragment identification and linker optimization of known fragment pairs.

Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.

Bridging covalent ligand discovery with chimeric degrader design has emerged as a mechanism to target proteins that lack enzymatic activity or are intractable. Here, the authors use biochemical and cellular tools to deconvolute the role of covalent modification in targeted protein degradation using Bruton’s tyrosine kinase.

Effective antivirals are critical for combatting SARS-CoV-2 infections. Here, the authors develop two orally available small molecules, which specifically inhibit the activity of the SARS-CoV-2 main protease and potently block the infectivity and replication of various SARS-CoV-2 strains in cells and mice.

Sila-substituted compounds have potential application in medicinal chemistry, but their preparation from the corresponding carbon analogues remains challenging. Here, the authors report the synthesis of sila-benzoazoles via hydrosilylation and rearrangement of benzoazoles; the reaction is enabled by a Lewis acid.

Deubiquitinases (DUBs) are key signaling enzymes, many of which lack selective inhibitors. Chan et al. pair a DUB-focused covalent library to mass spectrometry activity-based protein profiling, leading to selective hits against 23 endogenous DUBs and a first-in-class VCPIP1 probe with nanomolar potency.

Treatment of hypertension entails use of angiotensin-converting enzyme inhibitors. Here, the authors show a series of karnamicins with significant inhibitory activity and identify two unusual flavoprotein hydroxylases involved in the assembly of the fully-substituted hydroxypyridine core of karnamicins.

Polymer-based long-acting injectable drugs are a promising therapeutic strategy for chronic diseases. Here the authors use machine learning to inform the data-driven development of advanced drug formulations.

MraY is a membrane enzyme required for bacterial cell wall synthesis. Here, the authors modify sphaerimicins as antibacterials targeting it via structure-based design and synthesis through two key reactions, showing a platform for further development of MraY inhibitors as antibacterials.

Heparin is a family of complex carbohydrates binding to proteins to modulate cell activities. Here the authors report the synthesis, and conformations simulations of S-linked hemi-A heparosan [GlcA-S-GlcNAc]_n, a thio-glycosidic uncleavable polysaccharide, and test it as human heparanase inhibitor.

Chemical libraries with skeleton diversity are important for drug discovery. Here, the authors establish a synthetic methodology-based compound library (SMBL), and apply it to identify a small-molecule inhibitor to interrupt a challenging target:  the protein–protein interaction (PPI) of GIT1/β-Pix.

The rational design of PROTACs is difficult due to their obscure structure-activity relationship. Here the authors present a deep neural network model - DeepPROTACs - for predicting the degradation capacity of a proposed PROTAC molecule.

Here, the authors discover that ligandability of BTB domains correlates with the presence of μs-ms time scale dynamics. This finding suggests that protein dynamics may be a broadly applicable tool in drug discovery to assess the ligandability of novel and challenging targets.

Retrieval of a new starting active compound with a novel scaffold during early drug development is an important but challenging task. Here, the authors propose a generative deep learning model and by applying this model they discover a potent and highly selective RIPK1 inhibitor with a previously unreported scaffold.

Targeting cellular glucose metabolism is a therapeutic strategy in human diseases such as autoimmunity or cancer. Here, the authors demonstrate the druggability of phosphoglycolate phosphatase, and validate an alternative approach to control glycolysis.

Virtual screening of huge libraries is successful in identifying drug leads. Here, the authors describe a computational strategy, Chemical Space Docking, which combines docking with a reaction-based search of compounds, thereby enabling the exploration of billions of compounds and beyond.

The development of new classes of isosteres and building blocks is crucial to the advancement of medicinal chemistry programs. Here, the authors report the synthesis and development of ladderanes to act as replacements for meta-substituted aromatic rings and cyclohexanes.

Tuberculosis is a major cause of mortality, and the rise of drug-resistant strains of Mycobacterium tuberculosis requires the urgent development of safe and effective treatments. In this work, the authors develop a compound against lysyl-tRNA synthetase, demonstrating on-target mechanism of action and efficacy in vivo.

Protein degraders are an emerging drug modality; however, their properties lie beyond typical drug-like space. Here the authors report optimisation via structure-based exit vector and linker design towards the VHL-recruiting PROTAC ACBI2, an orally bioavailable and selective degrader of SMARCA2.

Therapeutic modulation of the complement system has gained interest over the past two decades. Here, the authors provide molecular-level insight into the mode-of-action, target selectivity and species specificity of the compstatin family of complement inhibitors, which entered the clinic in 2021.

LPA₁ is one of the GPCRs that are drug targets for various diseases. Here the authors report a cryo-EM structure of the active human LPA₁-G_i complex bound to an LPA analog with more potent activity against LPA₁ and clarified the ligand recognition mechanism.

Huang et al. discover a binding site on soluble RANKL that is not found on its membrane-bound homologue. A drug screening identified a small molecule (S3-15) that can target this binding site and has anti-osteoporotic but not immunosuppressive effects.

The development of antimalarials against the human liver and asexual blood stages is one of the top public health challenges. Here, the authors report a single-step biochemical assay for the characterization of prolyl-tRNA synthetase inhibitors, and develop high-affinity inhibitors for the enzyme, including elusive triple-site ligands.

The adenomatous polyposis coli (APC)–Asef protein interaction is essential for colorectal cancer metastasis. Here, the authors present the rational design of a sensitivity-enhanced tracer for fluorescence polarization assays, enabling them to discover more efficient APC–Asef interaction inhibitors.

Combination therapies simultaneously inhibiting different therapeutic targets in cancer is challenged by individual pharmacokinetic profiles. Here, the authors generate an orally provided multi-targeted kinase inhibitor that is lymphatic absorbed and increases survival in a murine model of myelofibrosis.

Wilcox et al. (2022) show that NMDA receptor channel blockers, some of which are clinically important drugs, can access their binding site via 2 routes: a well-known path from the extracellular solution, and another path through the plasma membrane.

Oligonucleotides targeting mRNA are promising therapeutic agents but suffer from poor bioavailability. Here, the authors develop reduced-charge oligonucleotides with artificial LNA-amide linkages with improved cell uptake and minimal structural deviation to the DNA:RNA duplex.

Macrocycles have potential as therapeutics, but their libraries are currently not large enough for high-throughput screening. Here, the authors show a combinatorial approach to generate a library of almost 20’000 macrocycles by conjugating carboxylic-acid fragments to macrocyclic scaffolds, identifying nanomolar inhibitors against thrombin and binders of MDM2.

The cytochrome P450 enzyme CYP1B1 is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. Here the authors describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6000-fold improvement in potency upon activation with low-energy (660 nm) light.

The current peripherally acting mu-opioid receptor antagonists present limited permeability and pharmacokinetic properties. Here, the authors develop a drug delivery approach based on AG10, which demonstrates the impact of mu-opioid receptors in the central nervous system in precipitating opioid-induced constipation.

The kinase DYRK2 is a known oncogene but its role in prostate cancer is unexplored. Here, the authors identify DYRK2 as a target for prostate cancer with a role in invasion and they discover a specific DYRK2 inhibitor that has good pharmacokinetics and efficacy in vivo.

It is currently difficult to synthesise NIR-II probes with good quantum yields, biocompatibility and pharmacokinetics. Here the authors report a strategy to alter these properties by modifying the protein coatings with biofunctional molecules, and generate long-wavelength fluorophores for in vivo imaging.

Inhibiting alpha-synuclein self-assembly into amyloid structures, associated with Parkinson’s disease, is a potential therapeutic intervention. Here, the authors identify the domains/sequences that are essential for alpha-synuclein aggregation and test the activity of foldamer-based antagonists to identify potential therapeutic targets.

Three covalent hybrid inhibitors of SARS-CoV-2 main protease (Mpro) have been designed and compared to Pfizer’s nirmatrelvir (PF-07321332), providing atomic and thermodynamic details of their binding to the enzyme, and antiviral potency.

Type I photodynamic therapy (PDT) sensitizers show good hypoxia tolerance but only few strategies are available for the design of purely organic Type I photosensitizers (PS). Here, the authors use biotinylation as design strategy to obtain PS-Biotin sensitizers with high efficiency for the generation of superoxide anion radicals and singlet oxygen.

Pepto-Bismol has been used to treat gastrointestinal disorders for over a century, yet the structure of its active ingredient is still under debate. Here, the authors apply electron crystallography to unveil the structure of bismuth subsalicylate.

Small molecule drugs promise to remain a valuable tool in controlling the ongoing COVID-19 pandemic. Here the authors describe optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for potential treatment of COVID-19.

Polymyxins are often the last therapeutic option for multidrug-resistant (MDR) bacteria, but have suboptimal safety and efficacy. Here the authors report the discovery and development of a synthetic lipopeptide with an improved safety and efficacy against top-priority MDR Gram-negative pathogens.

Protecting the whole small intestine from radiation-induced intestinal injury during the radiotherapy of abdominal or pelvic solid tumors remains an unmet clinical need. Here the authors use a natural microalga to readily construct an oral delivery system to achieve effective radioprotection for the small intestine.

Peptide fragments derived from the interfaces of protein-protein interactions (PPIs) provide useful templates for designing small molecule PPI inhibitors. Here, the authors utilize the multivalency of an MdmX-binding p53 peptide to develop a weak inhibitor of MdmX into potent Mdm2/MdmX inhibitors.

Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice.

Liu et al. report structures of human sphingosine 1-phosphate (S1P) receptor 1 (S1P₁) in complex with Gi and S1P or the multiple sclerosis (MS) drug Siponimod, as well as human lysophosphatidic acid (LPA) receptor 1 (LPA₁) in complex with Gi and LPA, revealing distinct conformations of the lysophospholipids interacting with their cognate GPCRs.

The molecular determinants of the residence time of a small molecule inhibitor at its target protein are not well understood. Here, Pantsar et al. show that the target protein’s conformational stability and solvent exposure are key factors governing the target residence time of kinase inhibitors.