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

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Exploration of Ultralarge Compound Collections for Drug Discovery

Journal of Chemical Information and Modeling, Journal Year: 2022, Volume and Issue: 62(9), P. 2021 - 2034

Published: April 14, 2022

Designing new medicines more cheaply and quickly is tightly linked to the quest of exploring chemical space widely efficiently. Chemical monumentally large, but recent advances in computer software hardware have enabled researchers navigate virtual spaces containing billions structures. This review specifically concerns collections many millions or even enumerated structures as well larger that are not fully enumerated. We present examples libraries means used construct them, we discuss technologies for searching huge combinatorially space. also cover navigation techniques consider approaches de novo drug design impact "autonomous laboratory" on synthesis designed compounds. Finally, summarize some other challenges opportunities future.

Language: Английский

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Late-stage Functionalization for Improving Drug-like Molecular Properties

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(13), P. 8127 - 8153

Published: June 7, 2023

The development of late-stage functionalization (LSF) methodologies, particularly C–H functionalization, has revolutionized the field organic synthesis. Over past decade, medicinal chemists have begun to implement LSF strategies into their drug discovery programs, allowing for process become more efficient. Most reported applications drugs and drug-like molecules been rapidly diversify screening libraries explore structure–activity relationships. However, there a growing trend toward use methodologies as an efficient tool improving molecular properties promising candidates. In this review, we comprehensively reviewed recent progress in emerging area. Particular emphasis is placed on case studies where multiple techniques were implemented generate library novel analogues with improved properties. We critically analyzed current scope improve commented how believe can transform future. Overall, aim provide comprehensive survey tools efficiently properties, anticipating its continued uptake programs.

Language: Английский

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Chemical Multiverse: An Expanded View of Chemical Space

Molecular Informatics, Journal Year: 2022, Volume and Issue: 41(11)

Published: Aug. 2, 2022

Technological advances and practical applications of the chemical space concept in drug discovery, natural product research, other research areas have attracted scientific community's attention. The large- ultra-large spaces are associated with significant increase number compounds that can potentially be made exist increasing experimental calculated descriptors, emerging encode molecular structure and/or property aspects molecules. Due to importance continued evolution compound libraries, herein, we discuss definitions proposed literature for emphasize convenience, discussed use complementary descriptors obtain a comprehensive view data sets. In this regard, introduce term multiverse refer analysis sets through several spaces, each defined by different set representations. is contrasted related idea: consensus space.

Language: Английский

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Photoinduced Ligand‐to‐Metal Charge Transfer of Carboxylates: Decarboxylative Functionalizations, Lactonizations, and Rearrangements

Advanced Synthesis & Catalysis, Journal Year: 2022, Volume and Issue: 364(24), P. 4189 - 4230

Published: Dec. 3, 2022

Abstract In the quest for sustainable processes, selection of resources and catalysts is central importance. Carboxylic acids, which are abundant, stable ideally biobased feedstocks, can be considered as attractive platforms towards a range functionalized molecules. A recent resurgence photoinduced ligand‐to‐metal charge transfer (LMCT) carboxylates led to tremendous developments in field earth‐abundant metal mediated, visible‐light induced (non)‐decarboxylative transformations carboxylic acids. These reactions combine use available starting materials, low‐consuming energy source abundant catalysts. Besides these undeniable advantages, they also provide mild, highly selective innovative conditions complex molecule functionalization. The objective this review give an overview advances LMCT with special focus on mechanistic aspects transformations. magnified image

Language: Английский

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Photochemistry in Pharmaceutical Development: A Survey of Strategies and Approaches to Industry-wide Implementation

Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(4), P. 831 - 846

Published: March 8, 2024

We present and analyze the results of a pharmaceutical industry-wide survey strategies approaches that companies have for implementing photochemical reactions in discovery chemistry, process development, commercial manufacturing. The questions encompass types pursue why, reactors (batch flow) used, how they are characterized photochemistry, scale-up reactions, prioritize resources developing among other topics. focuses on many these topics from perspectives chemists scientists to highlight similarities differences between their specific transformations materials construction used reactors. clearly demonstrate photochemistry is viable synthetic strategy producing active ingredients (APIs), all way commercialization. While more prevalent early stage indicate leveraging successful scale-ups later stages often using flow significant knowledge resulting experiences. Nevertheless, there still gaps adopting across development very limited experience discussing with regulatory agencies. Overall, offers considerable benefits synthesizing APIs API processes, such as greenness sustainability, shortening routes, potential improved product quality.

Language: Английский

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Photoredox‐Catalyzed Generation of Tertiary Anions from Primary Amines via a Radical Polar Crossover

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(6)

Published: Jan. 8, 2024

Abstract A method for the generation of tertiary carbanions via a deaminative radical‐polar crossover is reported using redox active imines from α‐tertiary primary amines. variety benzylic amines and amino esters can be used in this approach, with latter engaging novel “aza‐Reformatsky” reaction. Electronic trends correlate stability resulting carbanion reaction efficiency. The anions trapped different electrophiles including aldehydes, ketones, imines, Michael acceptors, H 2 O/D O. Selective anion formation achieved presence another equivalent or more acidic C−H bond both an inter‐ intramolecular fashion. Mechanistic studies suggest intermediacy discrete intermediate.

Language: Английский

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Docking 14 million virtual isoquinuclidines against the mu and kappa opioid receptors reveals dual antagonists-inverse agonists with reduced withdrawal effects

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Abstract Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration targeted isoquinuclidines. These “natural-product-like” rare in current functionally congested, making them as receptor probes. Using modular, four-component scheme, built docked virtual over 14.6 million isoquinuclidines against both µ- κ -opioid receptors (MOR KOR, respectively). Synthesis experimental testing 18 prioritized compounds found nine with low µM affinities. Structure-based optimization low- sub- nM antagonists inverse agonists targeting receptors. Cryo-electron microscopy (cryoEM) structures illuminate origins activity on each target. In mouse behavioral studies, member series joint MOR-antagonist KOR-inverse-agonist reversed morphine-induced analgesia, phenocopying MOR-selective anti-overdose agent naloxone. Encouragingly, new molecule induced less severe opioid-induced withdrawal symptoms compared to naloxone during precipitation, did not induce conditioned-place aversion, likely reflecting reduction dysphoria due compound’s KOR-inverse agonism. The strengths weaknesses bespoke docking, for opioid polypharmacology, will be considered.

Language: Английский

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Heterocyclic Assembly: An Underutilized Disconnection with Potential to Maximize High Fsp³ Chemical Space Exploration

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

From a retrosynthetic standpoint, functionalization or synthesis of heterocyclic cores are fundamental disconnections that chemists make. This manuscript highlights heterocycle as the strategic bond disconnection by leveraging ubiquitous building blocks, carboxylic acids and amines, for preparation in library-friendly format. formation strategy allows medicinal to access much wider chemical space, especially analogs with higher Fsp3 vs state-of-the-art methods. The direct impact on chemistry programs is underscored adapting miniaturizing N2-indazoles C2-benzimidazoles μ-scale parallel (PMC) libraries, affording similar success rate (80%) venerable Suzuki Buchwald-Hartwig libraries.

Language: Английский

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A Unified Method for Oxidative and Reductive Decarboxylative Arylation with Orange Light-Driven Ir/Ni Metallaphotoredox Catalysis

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(37), P. 25780 - 25787

Published: Sept. 5, 2024

Carboxylic acids and their derivatives are powerful building blocks in dual Ir/Ni metallaphotoredox methods of decarboxylative arylation due to abundance as feedstock compounds. However, the library accessible carboxylic is limited by trends radical stability, often necessitating development specific systems for challenging substrates. Herein, we disclose application a new Ir(III) photocatalyst low-energy orange light system with broad applicability activating both native redox-active esters (RAEs). This method represents first known example complementary oxidative reductive paradigms broadly similar reaction conditions, unlocking reactivity We further show wide scope aryl halide acid coupling partners regimes, added advantages over blue-light-catalyzed alkylation photosensitive

Language: Английский

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