DUckCov: a Dynamic Undocking-Based Virtual Screening Protocol for Covalent Binders

ChemMedChem
Moira RachmanGyörgy M Keserű

Abstract

Thanks to recent guidelines, the design of safe and effective covalent drugs has gained significant interest. Other than targeting non-conserved nucleophilic residues, optimizing the noncovalent binding framework is important to improve potency and selectivity of covalent binders toward the desired target. Significant efforts have been made in extending the computational toolkits to include a covalent mechanism of protein targeting, like in the development of covalent docking methods for binding mode prediction. To highlight the value of the noncovalent complex in the covalent binding process, here we describe a new protocol using tethered and constrained docking in combination with Dynamic Undocking (DUck) as a tool to privilege strong protein binders for the identification of novel covalent inhibitors. At the end of the protocol, dedicated covalent docking methods were used to rank and select the virtual hits based on the predicted binding mode. By validating the method on JAK3 and KRas, we demonstrate how this fast iterative protocol can be applied to explore a wide chemical space and identify potent targeted covalent inhibitors.

References

Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
Apr 13, 2005·Biochemistry·James G Robertson
Feb 20, 2007·Journal of Chemical Information and Modeling·Christopher R CorbeilNicolas Moitessier
Mar 28, 2008·Annual Review of Biochemistry·Benjamin F CravattJohn W Kozarich
May 12, 2009·Drug Discovery Today·Wolfgang FeckeFreddy Heitz
Jun 23, 2009·Nature Reviews. Immunology·Yrina RochmanWarren J Leonard
Jul 20, 2010·Future Medicinal Chemistry·Douglas S JohnsonBenjamin F Cravatt
Nov 19, 2010·Nature·Eranthie WeerapanaBenjamin F Cravatt
Apr 2, 2011·Nature Reviews. Drug Discovery·Juswinder SinghAdrian Whitty
Oct 11, 2011·Journal of the American Chemical Society·Peter SchmidtkeXavier Barril
Feb 27, 2013·Chemistry & Biology·Qingsong LiuNathanael S Gray
Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
Dec 10, 2013·Bioorganic & Medicinal Chemistry Letters·Robert MahCynthia M Shafer
Apr 12, 2014·PLoS Computational Biology·Sergio Ruiz-CarmonaS David Morley
Jun 12, 2014·Journal of Chemical Information and Modeling·Kai ZhuEdward Harder
Jun 17, 2014·Journal of Chemical Information and Modeling·Dora Toledo WarshaviakOri Kalid
Aug 26, 2014·Journal of Medicinal Chemistry·Christian JöstChristian D Klein
Oct 27, 2014·Nature Chemical Biology·Nir LondonJack Taunton
Dec 17, 2014·Bioinformatics·Woonghee LeeJohn L Markley
Dec 30, 2014·Journal of Chemical Information and Modeling·Christoph ScholzBoris Schmidt
Jan 31, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hezekiel Mathambo KumaloMahmoud E S Soliman
Jun 25, 2015·Protein Science : a Publication of the Protein Society·Giulia BiancoArthur J Olson
Feb 22, 2017·Nature Chemistry·Sergio Ruiz-CarmonaXavier Barril
Mar 23, 2017·Journal of Medicinal Chemistry·Zheng ZhaoPhilip E Bourne
Apr 7, 2017·PloS One·Johanna M JansenStephen Hardy
May 13, 2017·Journal of Medicinal Chemistry·Eva NittingerMatthias Rarey
Nov 14, 2017·Journal of Chemical Information and Modeling·Richard LonsdaleRichard A Ward
Jan 11, 2018·Journal of Chemical Information and Modeling·Chimno I NnadiNir London
Jun 12, 2018·Journal of Chemical Information and Modeling·Andrea ScarpinoGyörgy M Keserű

❮ Previous
Next ❯

Citations

Jan 30, 2020·Physical Chemistry Chemical Physics : PCCP·Zhe WangTingjun Hou
Jul 28, 2020·Cancer Metastasis Reviews·Kinga NyíriBeáta G Vértessy
Dec 24, 2020·Expert Opinion on Drug Discovery·Julio Caballero
Sep 12, 2019·Journal of Chemical Theory and Computation·Indrajit Deb, Aaron T Frank
Aug 31, 2021·RSC Chemical Biology·Wenchao LuNathanael S Gray
Sep 29, 2021·Nucleic Acids Research·Mingjie GaoStefan Günther

❮ Previous
Next ❯

Methods Mentioned

BETA
NMR
FRET

Software Mentioned

FITTED
Pro
DUckCov
SMILES
CovDock Virtual screening
MOE
VS
NMRFAM
Schrödinger
ICM

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Hezekiel Mathambo KumaloMahmoud E S Soliman
Journal of Chemical Information and Modeling
Ashutosh KumarKam Y J Zhang
© 2022 Meta ULC. All rights reserved