Self-Driving Laboratories for Chemistry and Materials Science

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(16), P. 9633 - 9732

Published: Aug. 13, 2024

Self-driving laboratories (SDLs) promise an accelerated application of the scientific method. Through automation experimental workflows, along with autonomous planning, SDLs hold potential to greatly accelerate research in chemistry and materials discovery. This review provides in-depth analysis state-of-the-art SDL technology, its applications across various disciplines, implications for industry. additionally overview enabling technologies SDLs, including their hardware, software, integration laboratory infrastructure. Most importantly, this explores diverse range domains where have made significant contributions, from drug discovery science genomics chemistry. We provide a comprehensive existing real-world examples different levels automation, challenges limitations associated each domain.

Language: Английский

---

Evolution of the SARS-CoV-2 Omicron Variants: Genetic Impact on Viral Fitness

Viruses, Journal Year: 2024, Volume and Issue: 16(2), P. 184 - 184

Published: Jan. 25, 2024

Over the last three years, pandemic of COVID-19 has had a significant impact on people’s lives and global economy. The incessant emergence variant strains compounded challenges associated with management COVID-19. As predominant from late 2021 to present, Omicron its sublineages, through continuous evolution, have demonstrated iterative viral fitness. comprehensive elucidation biological implications that catalyzed this evolution remains incomplete. In accordance extant research evidence, we provide review subvariants Omicron, delineating alterations in immune evasion, cellular infectivity, cross-species transmission potential. This seeks clarify underpinnings biology within SARS-CoV-2, thereby providing foundation for strategic considerations post-pandemic era

Language: Английский

---

Structural biology of SARS-CoV-2 Mpro and drug discovery

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 82, P. 102667 - 102667

Published: Aug. 4, 2023

Language: Английский

---

Structure-based virtual screening of vast chemical space as a starting point for drug discovery

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 87, P. 102829 - 102829

Published: June 6, 2024

Structure-based virtual screening aims to find molecules forming favorable interactions with a biological macromolecule using computational models of complexes. The recent surge commercially available chemical space provides the opportunity search for ligands therapeutic targets among billions compounds. This review offers compact overview structure-based screens vast spaces, highlighting successful applications in early drug discovery therapeutically important such as G protein-coupled receptors and viral enzymes. Emphasis is placed on strategies explore ultra-large libraries synergies emerging machine learning techniques. current opportunities future challenges are discussed, indicating that this approach will play an role next-generation pipeline.

Language: Английский

---

An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(738)

Published: March 13, 2024

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing severity COVID-19, but presence resistance-conferring mutations sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized covalent hepatitis C virus inhibitor boceprevir (BPV) could serve basis for orally bioavailable inhibit SARS-CoV-2 M more efficiently than existing drugs. Performing structure-guided modifications BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, pharmacokinetics, therapeutic efficacy similar or superior to those NTV. A crucial feature ML2006a4 is derivatization ketoamide reactive group improves cell permeability bioavailability. Last, was found be less sensitive several cause resistance NTV ETV occur natural population. Thus, anticipatory design can preemptively address potential mechanisms expand treatment options variants.

Language: Английский

---

Fragmenstein: predicting protein-ligand structures of compounds derived from known crystallographic fragment hits using a strict conserved-binding–based methodology

Published: Feb. 26, 2024

Current strategies centred on either merging or linking initial hits from fragment-based drug design (FBDD) crystallographic screens ignore 3D structural information. We show that an algorithmic approach (Fragmenstein) ‘stitches’ the ligand atoms this information together can provide more accurate and reliable predictions for protein-ligand complex conformation than existing methods such as pharmacophore-constrained docking. This works under assumption of conserved binding: when a larger molecule is designed containing fragment hit, common substructure between two will adopt same binding mode. Fragmenstein takes coordinates ligands experimental screen stitches to produce novel merged compound, uses them predict provided compound. The compound then energy minimised strong constraints obtain structurally plausible method successful in showing importance using known binders predicting derivative compounds through retrospective analysis COVID Moonshot data. It has also had real-world application hit-to-lead screening, yielding sub-micromolar merger parent single round.

Language: Английский

---

Toward physics‐based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants

Protein Science, Journal Year: 2024, Volume and Issue: 33(3)

Published: Feb. 15, 2024

The goal of precision medicine is to utilize our knowledge the molecular causes disease better diagnose and treat patients. However, there a substantial mismatch between small number food drug administration (FDA)-approved drugs annotated coding variants compared needs medicine. This review introduces concept physics-based medicine, scalable framework that promises improve understanding sequence-function relationships accelerate discovery. We show accounting for ensemble structures protein adopts in solution with computer simulations overcomes many limitations imposed by assuming single structure. highlight studies dynamics recent methods analysis structural ensembles. These demonstrate differences conformational distributions predict functional within families variants. Thanks new computational tools are providing unprecedented access ensembles, this insight may enable accurate predictions variant pathogenicity entire libraries further explicitly like alchemical free energy calculations or docking Markov state models, can uncover novel lead compounds. To conclude, we cryptic pockets, cavities absent experimental structures, provide an avenue target proteins currently considered undruggable. Taken together, provides roadmap field science

Language: Английский

---

In silico screening of LRRK2 WDR domain inhibitors using deep docking and free energy simulations

Chemical Science, Journal Year: 2024, Volume and Issue: 15(23), P. 8800 - 8812

Published: Jan. 1, 2024

In this work, we combined Deep Docking and free energy MD simulations for the in silico screening experimental validation potential inhibitors of leucine rich repeat kinase 2 (LRRK2) targeting WD40 (WDR) domain.

Language: Английский

---

Fragmenstein: predicting protein–ligand structures of compounds derived from known crystallographic fragment hits using a strict conserved-binding–based methodology

Journal of Cheminformatics, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 13, 2025

Language: Английский

---

Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 13, 2025

The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents systematic design quinoline-containing papain-like protease (PLpro) inhibitors as potential antiviral drug candidates. By leveraging recently discovered Val70Ub binding site in PLpro, we designed a series quinoline analogs demonstrating potent PLpro inhibition and activity. Notably, X-ray crystal structures 6 lead compounds reveal that 2-aryl substitution can occupy either expected or BL2 groove flipped orientation. vivo Jun13296 exhibits favorable pharmacokinetic properties against nirmatrelvir-resistant mutants. In mouse model infection, treatment with significantly improves survival, reduces body weight loss lung viral titers, prevents tissue damage. These results underscore promising candidates, instilling hope for future treatment. inhibitor, Jun13296, displays efficacy infection inhibits mutants, rendering it candidate.

Language: Английский

---