Computational approaches streamlining drug discovery

Nature, Journal Year: 2023, Volume and Issue: 616(7958), P. 673 - 685

Published: April 26, 2023

Computer-aided drug discovery has been around for decades, although the past few years have seen a tectonic shift towards embracing computational technologies in both academia and pharma. This is largely defined by flood of data on ligand properties binding to therapeutic targets their 3D structures, abundant computing capacities advent on-demand virtual libraries drug-like small molecules billions. Taking full advantage these resources requires fast methods effective screening. includes structure-based screening gigascale chemical spaces, further facilitated iterative approaches. Highly synergistic are developments deep learning predictions target activities lieu receptor structure. Here we review recent advances technologies, potential reshaping whole process development, as well challenges they encounter. We also discuss how rapid identification highly diverse, potent, target-selective ligands protein can democratize process, presenting new opportunities cost-effective development safer more small-molecule treatments. Recent approaches application streamlining discussed.

Language: Английский

---

Electrochemical Late-Stage Functionalization

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(19), P. 11269 - 11335

Published: Sept. 26, 2023

Late-stage functionalization (LSF) constitutes a powerful strategy for the assembly or diversification of novel molecular entities with improved physicochemical biological activities. LSF can thus greatly accelerate development medicinally relevant compounds, crop protecting agents, and functional materials. Electrochemical synthesis has emerged as an environmentally friendly platform transformation organic compounds. Over past decade, electrochemical late-stage (eLSF) gained major momentum, which is summarized herein up to February 2023.

Language: Английский

---

Overcoming the limitations of Kolbe coupling with waveform-controlled electrosynthesis

Science, Journal Year: 2023, Volume and Issue: 380(6640), P. 81 - 87

Published: April 6, 2023

The Kolbe reaction forms carbon-carbon bonds through electrochemical decarboxylative coupling. Despite more than a century of study, the has seen limited applications owing to extremely poor chemoselectivity and reliance on precious metal electrodes. In this work, we present simple solution long-standing challenge: Switching potential waveform from classical direct current rapid alternating polarity renders various functional groups compatible enables sustainable carbon-based electrodes (amorphous carbon). This breakthrough enabled access valuable molecules that range useful unnatural amino acids promising polymer building blocks readily available carboxylic acids, including biomass-derived acids. Preliminary mechanistic studies implicate role in modulating local pH around crucial acetone as an unconventional solvent for reaction.

Language: Английский

---

Facile and general electrochemical deuteration of unactivated alkyl halides

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: June 30, 2022

Abstract Herein, a facile and general electroreductive deuteration of unactivated alkyl halides (X = Cl, Br, I) or pseudo-halides OMs) using D 2 O as the economical deuterium source was reported. In addition to primary secondary halides, sterically hindered tertiary chlorides also work very well, affording target deuterodehalogenated products with excellent efficiency incorporation. More than 60 examples are provided, including late-stage dehalogenative natural products, pharmaceuticals, their derivatives, all incorporation (up 99% D), demonstrating potential utility developed method in organic synthesis. Furthermore, does not require external catalysts tolerates high current, showing possible use industrial applications.

Language: Английский

---

CO2-mediated organocatalytic chlorine evolution under industrial conditions

Nature, Journal Year: 2023, Volume and Issue: 617(7961), P. 519 - 523

Published: May 17, 2023

Language: Английский

---

Nickel-Catalyzed Enantioselective Electrochemical Reductive Cross-Coupling of Aryl Aziridines with Alkenyl Bromides

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(11), P. 6270 - 6279

Published: March 7, 2023

An electrochemically driven nickel-catalyzed enantioselective reductive cross-coupling of aryl aziridines with alkenyl bromides has been developed, affording enantioenriched β-aryl homoallylic amines excellent E-selectivity. This electroreductive strategy proceeds in the absence heterogeneous metal reductants and sacrificial anodes by employing constant current electrolysis an undivided cell triethylamine as a terminal reductant. The reaction features mild conditions, remarkable stereocontrol, broad substrate scope, functional group compatibility, which was illustrated late-stage functionalization bioactive molecules. Mechanistic studies indicate that this transformation conforms stereoconvergent mechanism aziridine is activated through nucleophilic halide ring-opening process.

Language: Английский

---

Decarboxylative Cross-Coupling: A Radical Tool in Medicinal Chemistry

ACS Medicinal Chemistry Letters, Journal Year: 2022, Volume and Issue: 13(9), P. 1413 - 1420

Published: Aug. 10, 2022

Carboxylic acids, the most versatile and ubiquitous diversity input used in medicinal chemistry for canonical polar bond constructions such as amide synthesis, can now be employed a fundamentally different category of reaction to make C-C bonds by harnessing power radicals. This outlook serves user-guide aid practitioners both design syntheses that leverage simplifying this disconnection precise tactics enable them. Taken together, emerging area holds potential rapidly accelerate access chemical space value modern chemistry.

Language: Английский

---

Electroreductive Cross‐Electrophile Coupling (eXEC) Reactions

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(45)

Published: June 16, 2023

Abstract Electrochemistry utilizes electrons as a potent, controllable, and traceless alternative to chemical oxidants or reductants, typically offers more sustainable option for achieving selective organic synthesis. Recently, the merger of electrochemistry with readily available electrophiles has been recognized viable increasingly popular methodology efficiently constructing challenging C−C C‐heteroatom bonds in manner complex molecules. In this mini‐review, we have systematically summarized most recent advances electroreductive cross‐electrophile coupling (eXEC) reactions during last decade. Our focus on electrophiles, including aryl alkyl (pseudo)halides, well small molecules such CO 2 , SO D O.

Language: Английский

---

Electrocarboxylation of Aryl Epoxides with CO₂for the Facile and Selective Synthesis of β‐Hydroxy Acids

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(38)

Published: July 30, 2022

Abstract Herein, an efficient and facile approach to valuable β‐hydroxy acid derivatives from readily available aryl epoxides CO 2 with high chemo‐ regioselectivity under mild sustainable electrochemical conditions is described. This showed broad substrate scope good functional‐group compatibility. In addition epoxides, four‐ six‐membered cyclic ethers could all be tolerated in the reaction provide synthetically useful hydroxy acids efficiency. Further late‐stage carboxylation of complex molecules drug demonstrated its potential application pharmaceutical industry. Mechanistic studies disclosed possible pathways.

Language: Английский

---

Nickel Catalysis via S_H2 Homolytic Substitution: The Double Decarboxylative Cross-Coupling of Aliphatic Acids

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(46), P. 21278 - 21286

Published: Nov. 14, 2022

Cross-coupling platforms are traditionally built around a sequence of closed-shell steps, such as oxidative addition, transmetalation, and reductive elimination. Herein, we describe dual photo/nickel catalytic manifold that performs cross-coupling via complementary involving free radical generation, sorting selective binding to Ni(II) center, bimolecular homolytic substitution (SH2) at high-valent nickel-alkyl complex. This enables the hitherto elusive diverse aliphatic carboxylic acids generate valuable C(sp3)-C(sp3)-products. Notably, powerful SH2 mechanism provides general access sterically encumbered quaternary carbon centers, addressing long-standing challenge in fragment coupling chemistry.

Language: Английский

---