What coronavirus 3C‐like protease tells us: From structure, substrate selectivity, to inhibitor design DOI Open Access
Muya Xiong, Haixia Su, Wenfeng Zhao

и другие.

Medicinal Research Reviews, Год журнала: 2021, Номер 41(4), С. 1965 - 1998

Опубликована: Янв. 18, 2021

Abstract The emergence of a variety coronaviruses (CoVs) in the last decades has posed huge threats to human health. Especially, ongoing pandemic coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2) led more than 70 million infections and over 1.6 deaths worldwide past few months. None efficacious antiviral agents against CoVs have been approved yet. 3C‐like protease (3CL pro ) is an attractive target for intervention due its essential role processing polyproteins translated from viral RNA, conserved structural feature substrate specificity among spite sequence variation. This review focuses on all available crystal structures 12 CoV 3CL s their inhibitors, intends provide comprehensive understanding this multiple aspects including features, specificity, inhibitor binding modes, importantly, recapitulate similarity diversity different structure–activity relationship various types inhibitors. Such attempt could gain deep insight into inhibition mechanisms drive future structure‐based drug discovery targeting s.

Язык: Английский

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology DOI
Matthias Gehringer, Stefan Laufer

Journal of Medicinal Chemistry, Год журнала: 2018, Номер 62(12), С. 5673 - 5724

Опубликована: Дек. 19, 2018

Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is predominant strategy in TCI development. The recent ascent drugs has stimulated considerable efforts characterize alternative warheads for covalent-reversible irreversible engagement as well acids. This Perspective article provides an overview warheads-beyond amides-recently used design targeted ligands. Promising groups that have not yet demonstrated their utility development also highlighted. Special emphasis placed on discussion reactivity case studies illustrating applications medicinal chemistry chemical biology.

Язык: Английский

Процитировано

584

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease DOI Creative Commons
A. Douangamath, D. Fearon,

Paul Gehrtz

и другие.

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Окт. 7, 2020

Abstract COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through combined mass spectrometry X-ray approach SARS-CoV-2 main protease, one two cysteine viral proteases essential replication. Our crystallographic identified 71 hits that span entire active site, as well 3 at dimer interface. These structures reveal routes to rapidly develop more potent inhibitors merging covalent fragment hits; series low-reactivity, tractable progressed discover improved binders. offer unprecedented structural reactivity information on-going structure-based drug design protease.

Язык: Английский

Процитировано

487

Advances in covalent drug discovery DOI Open Access
Lydia Boike, Nathaniel J. Henning, Daniel K. Nomura

и другие.

Nature Reviews Drug Discovery, Год журнала: 2022, Номер 21(12), С. 881 - 898

Опубликована: Авг. 25, 2022

Язык: Английский

Процитировано

485

Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway DOI Creative Commons
Kari J. Kurppa, Yao Liu, Ciric To

и другие.

Cancer Cell, Год журнала: 2020, Номер 37(1), С. 104 - 122.e12

Опубликована: Янв. 1, 2020

Язык: Английский

Процитировано

369

Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase DOI
Yunhang Guo, Ye Liu, Nan Hu

и другие.

Journal of Medicinal Chemistry, Год журнала: 2019, Номер 62(17), С. 7923 - 7940

Опубликована: Авг. 5, 2019

Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis B-cell lymphomas, suggesting that inhibition BTK is useful the treatment hematological malignancies. The discovery a more selective on-target covalent inhibitor high value. Herein, we disclose and preclinical characterization potent, selective, irreversible as our clinical candidate by using vitro potency, selectivity, pharmacokinetics (PK), vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against excellent selectivity over other TEC, EGFR Src family kinases, (ii) desirable ADME, mice efficacy OCI-LY10 xenograft models.

Язык: Английский

Процитировано

283

Empirical Scoring Functions for Structure-Based Virtual Screening: Applications, Critical Aspects, and Challenges DOI Creative Commons
Isabella Alvim Guedes,

Felipe Siconha S. Pereira,

Laurent E. Dardenne

и другие.

Frontiers in Pharmacology, Год журнала: 2018, Номер 9

Опубликована: Сен. 24, 2018

Structure-based virtual screening is a widely used approach that employs the knowledge of three- dimensional structure target interest in design new lead compounds from large-scale molecular docking experiments. Through prediction binding mode and affinity small molecule within site interest, it possible to understand important properties related process. Empirical scoring functions are for pose prediction. Although performed with satisfactory accuracy, correct still challenging task crucial success structure-based There several efforts distinct fronts develop even more sophisticated accurate models filtering ranking large libraries compounds. This paper will cover some recent successful applications methodological advances, including strategies explore ligand entropy solvent effects, training machine-learning techniques use quantum mechanics. Particular emphasis be given discussion critical aspects further directions development empirical functions.

Язык: Английский

Процитировано

263

Advances in covalent kinase inhibitors DOI

Ayah Abdeldayem,

Yasir S. Raouf, Stefan N. Constantinescu

и другие.

Chemical Society Reviews, Год журнала: 2020, Номер 49(9), С. 2617 - 2687

Опубликована: Янв. 1, 2020

Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords unique set of advantages as well challenges relative to their non-covalent counterpart. After reversible protein target recognition and binding, irreversibly modify proximal nucleophilic residue on via reaction with an electrophile. To date, acrylamide group remains predominantly employed electrophile CKI development, its incorporation majority clinical candidates FDA approved therapies. Nonetheless, recent years considerable efforts ensued characterize alternative electrophiles that exhibit irreversible or reversibly binding mechanisms towards cysteine thiols other amino acids. This review article provides comprehensive overview CKIs reported literature over decade period, 2007-2018. Emphasis is placed rationale behind warhead choice, optimization approach, inhibitor design. Current are also highlighted, addition detailed analysis common trends themes observed within listed data set.

Язык: Английский

Процитировано

257

A Perspective on Multi-target Drugs for Alzheimer’s Disease DOI
Ondřej Benek, Jan Korábečný, Ondřej Soukup

и другие.

Trends in Pharmacological Sciences, Год журнала: 2020, Номер 41(7), С. 434 - 445

Опубликована: Май 21, 2020

Язык: Английский

Процитировано

204

Next generation 3D pharmacophore modeling DOI Creative Commons
David Schaller,

Dora Šribar,

Theresa Noonan

и другие.

Wiley Interdisciplinary Reviews Computational Molecular Science, Год журнала: 2020, Номер 10(4)

Опубликована: Фев. 26, 2020

Abstract 3D pharmacophore models are three‐dimensional ensembles of chemically defined interactions a ligand in its bioactive conformation. They represent an elegant way to decipher encoded information and have therefore become valuable tool drug design. In this review, we provide overview on the basic concept method summarize key studies for applying virtual screening mechanistic protein functionality. Moreover, discuss recent developments field. The combination with molecular dynamics simulations could be quantum leap forward since these approaches consider macromolecule–ligand as dynamic show physiologically relevant interaction pattern. Other trends include efficient usage machine learning artificial intelligence applications or freely accessible web servers modeling. that modeling is vibrant field various discovery beyond. This article categorized under: Computer Information Science > Chemoinformatics Algorithms Programming Molecular Statistical Mechanics Interactions

Язык: Английский

Процитировано

202

Mechanistic enzymology in drug discovery: a fresh perspective DOI
Geoffrey A. Holdgate, Thomas D. Meek,

Rachel L. Grimley

и другие.

Nature Reviews Drug Discovery, Год журнала: 2017, Номер 17(2), С. 115 - 132

Опубликована: Ноя. 30, 2017

Язык: Английский

Процитировано

187