Macrocycles in Drug Discovery─Learning from the Past for the Future

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(8), P. 5377 - 5396

Published: April 5, 2023

We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs mainly infectious disease oncology, while oncology is major indication for candidates Most bind targets that difficult binding sites. Natural products provided 80–90% of whereas ChEMBL less complex structures. Macrocycles usually reside beyond Rule 5 chemical space, but 30–40% orally bioavailable. Simple bi-descriptor models, i.e., HBD ≤ 7 combination with either MW < 1000 Da or cLogP > 2.5, distinguished orals from parenterals can be as filters design. propose breakthroughs conformational analysis inspiration natural will further improve de novo design macrocycles.

Language: Английский

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“Magic Chloro”: Profound Effects of the Chlorine Atom in Drug Discovery

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(8), P. 5305 - 5331

Published: April 4, 2023

Chlorine is one of the most common atoms present in small-molecule drugs beyond carbon, hydrogen, nitrogen, and oxygen. There are currently more than 250 FDA-approved chlorine-containing drugs, yet beneficial effect chloro substituent has not been reviewed. The seemingly simple substitution a hydrogen atom (R = H) with chlorine Cl) can result remarkable improvements potency up to 100,000-fold lead profound effects on pharmacokinetic parameters including clearance, half-life, drug exposure vivo. Following literature terminology "magic methyl effect" term coined herein. Although reports 500-fold or 1000-fold often serendipitous discoveries that be considered "magical" rather planned, hypotheses made explain magic lessons accelerate cycle discovery.

Language: Английский

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The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development

JACS Au, Journal Year: 2023, Volume and Issue: 3(3), P. 715 - 735

Published: Feb. 27, 2023

Biocatalysis is a highly valued enabling technology for pharmaceutical research and development as it can unlock synthetic routes to complex chiral motifs with unparalleled selectivity efficiency. This perspective aims review recent advances in the implementation of biocatalysis across early late-stage focus on processes preparative-scale syntheses.

Language: Английский

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Biocatalytic amide bond formation

Green Chemistry, Journal Year: 2023, Volume and Issue: 25(8), P. 2958 - 2970

Published: Jan. 1, 2023

The state-of-the-art of biocatalytic amide bond formation is discussed with the help a manually curated database enzymatic amidation reactions.

Language: Английский

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Learning from Protein Engineering by Deconvolution of Multi‐Mutational Variants

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(36)

Published: June 17, 2024

Abstract This review analyzes a development in biochemistry, enzymology and biotechnology that originally came as surprise. Following the establishment of directed evolution stereoselective enzymes organic chemistry, concept partial or complete deconvolution selective multi‐mutational variants was introduced. Early experiments led to finding mutations can interact cooperatively antagonistically with one another, not just additively. During past decade, this phenomenon shown be general. In some studies, molecular dynamics (MD) quantum mechanics/molecular mechanics (QM/MM) computations were performed order shed light on origin non‐additivity at all stages an evolutionary upward climb. Data used construct unique multi‐dimensional rugged fitness pathway landscapes, which provide mechanistic insights different from traditional landscapes. Along related line, biochemists have long tested result introducing two point enzyme for reasons, followed by comparison respective double mutant so‐called cycles, showed only additive effects, but more recently also uncovered cooperative antagonistic non‐additive effects. We conclude suggestions future work, call unified overall picture epistasis.

Language: Английский

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Discovery of plant-derived anti-tumor natural products: Potential leads for anti-tumor drug discovery

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 142, P. 106957 - 106957

Published: Nov. 5, 2023

Language: Английский

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Enzymatic Bioconjugation: A Perspective from the Pharmaceutical Industry

JACS Au, Journal Year: 2023, Volume and Issue: 3(5), P. 1267 - 1283

Published: May 4, 2023

Enzymes have firmly established themselves as bespoke catalysts for small molecule transformations in the pharmaceutical industry, from early research and development stages to large-scale production. In principle, their exquisite selectivity rate acceleration can also be leveraged modifying macromolecules form bioconjugates. However, available face stiff competition other bioorthogonal chemistries. this Perspective, we seek illuminate applications of enzymatic bioconjugation an expanding palette new drug modalities. With these applications, wish highlight some examples current successes pitfalls using enzymes along pipeline try illustrate opportunities further development.

Language: Английский

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Natural Product Synthesis in the 21st Century: Beyond the Mountain Top

ACS Central Science, Journal Year: 2024, Volume and Issue: 10(3), P. 519 - 528

Published: Feb. 14, 2024

Research into natural products emerged from humanity's curiosity about the nature of matter and its role in materia medica diverse civilizations. Plants fungi, particular, supplied materials that altered behavior, perception, well-being profoundly. Many active principles remain well-known today: strychnine, morphine, psilocybin, ephedrine. The potential to circumvent constraints supply explore properties these led field product synthesis. This research delivered new molecules with properties, but also fundamental insights chemistry nonmetal elements H, C, N, O, P, S, Se, their combinations, i.e., organic chemistry. It a potent culture focused on bigger races finish line, perhaps at expense actionable next steps. About 20 years ago, began contract United States. solely chemical reaction development, especially catalysis, filled void. After all, reactions mechanistic insight could be immediately implemented by community, so it became hard justify lengthy procurement complex molecule sat freezer unused. shift coincided divestment portfolios pharmaceutical companies an emphasis academic applications-driven research, more science. However, as bioassays tools biology become widespread, synthesis finds powerful ally allows us better deliver premise field. And hard-won can encoded digitally, mined data science, applied challenges, chemists perturb even surpass products. 21st century promises developments, both interface biology, if community scientists fosters growth. essay tries contextualize for broad audience, looks ahead transformation coming years, expects future bright.

Language: Английский

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Substrate Conformational Switch Enables the Stereoselective Dimerization in P450 NascB: Insights from Molecular Dynamics Simulations and Quantum Mechanical/Molecular Mechanical Calculations

JACS Au, Journal Year: 2024, Volume and Issue: 4(4), P. 1591 - 1604

Published: April 9, 2024

P450 NascB catalyzes the coupling of cyclo-(l-tryptophan-l-proline) (1) to generate (−)-naseseazine C (2) through intramolecular C–N bond formation and intermolecular C–C coupling. A thorough understanding its catalytic mechanism is crucial for engineering or design P450-catalyzed dimerization reactions. By employing MD simulations, QM/MM calculations, enhanced sampling, we assessed various mechanisms from recent works. Our study demonstrates that most favorable pathway entails transfer a hydrogen atom N7–H Cpd I. Subsequently, there conformational change in substrate radical, shifting it Re-face Si-face N7 Substrate 1. The conformation 1 stabilized by protein environment π–π stacking interaction between indole ring heme porphyrin. subsequent C3–C6′ radical 2 occurs via attack mechanism. switch not only lowers barrier but also yields correct stereoselectivity observed experiments. In addition, evaluated reactivity ferric-superoxide species, showing reactive enough initiate abstraction NH group substrate. simulation provides comprehensive mechanistic insight into how enzyme precisely controls both cyclization current findings align with available experimental data, emphasizing pivotal role dynamics governing catalysis.

Language: Английский

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Future challenges and opportunities with fluorine in drugs?

Medicinal Chemistry Research, Journal Year: 2023, Volume and Issue: 32(7), P. 1231 - 1234

Published: June 15, 2023

Language: Английский

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