p38α MAPK and Type I Inhibitors: Binding Site Analysis and Use of Target Ensembles in Virtual Screening

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Andrea AstolfiVioletta Cecchetti

Abstract

Mitogen-activated protein kinase p38α plays an essential role in the regulation of pro-inflammatory signaling, and selective blockade of this kinase could be efficacious in many pathological processes. Despite considerable research efforts focused on the discovery and development of p38α MAPK inhibitors, no drug targeting this protein has been approved for clinical use so far. We herein analyze the available crystal structures of p38α MAPK in complex with ATP competitive type I inhibitors, getting insights into ATP binding site conformation and its influence on automated molecular docking results. The use of target ensembles, rather than single conformations, resulted in a performance improvement in both the ability to reproduce experimental bound conformations and the capability of mining active molecules from compound libraries. The information gathered from this study can be exploited in structure-based drug discovery programs having as the ultimate aim the identification of novel p38α MAPK type I inhibitors.

References

Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Dec 26, 2001·Chemical Reviews·J A Adams
Mar 16, 2002·Nature Structural Biology·Christopher PargellisJohn Regan
May 23, 2002·Cell·Morgan Huse, John Kuriyan
Aug 5, 2003·Nature Structural Biology·Catherine E FitzgeraldGiovanna Scapin
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
Jan 26, 2005·Journal of Chemical Information and Modeling·John J Irwin, Brian K Shoichet
Sep 24, 2005·Current Topics in Medicinal Chemistry·Stephen T Wrobleski, Arthur M Doweyko
Nov 12, 2005·Medicinal Research Reviews·Gerd Wagner, Stefan Laufer
Dec 24, 2005·Angewandte Chemie·Martin VogtherrHarald Schwalbe
Jun 20, 2006·Nature Chemical Biology·Yi Liu, Nathanael S Gray
Dec 13, 2006·Biophysical Journal·Amarda ShehuCecilia Clementi
Jun 2, 2007·ChemMedChem·Simona Margutti, Stefan A Laufer
Sep 28, 2007·Journal of Computer-aided Molecular Design·John C ShelleyMakoto Uchimaya
Nov 9, 2007·Journal of Medicinal Chemistry·Rameshwar U KadamNilanjan Roy
May 13, 2009·Journal of Chemical Information and Modeling·Thomas A Halgren
Aug 12, 2009·Trends in Molecular Medicine·Lydia R CoulthardSusan A Burchill
Dec 3, 2009·Journal of the American Chemical Society·Jeffrey R SimardDaniel Rauh
Dec 17, 2009·Journal of Medicinal Chemistry·Fabio ZuccottoMauro Angiolini
Jul 1, 2010·Current Medicinal Chemistry·L GarutiG Bottegoni
Oct 26, 2010·Trends in Biochemical Sciences·Susan S Taylor, Alexandr P Kornev
Mar 31, 2011·Future Medicinal Chemistry·Mauro Angiolini
Oct 21, 2011·Chembiochem : a European Journal of Chemical Biology·Gerd Nielsen, Harald Schwalbe
Mar 23, 2012·Journal of Chemical Information and Modeling·Thomas SciorDimitris K Agrafiotis
Apr 10, 2012·Journal of Chemical Information and Modeling·Oliver KorbJason C Cole
Apr 25, 2012·Journal of Computer-aided Molecular Design·Natalie B VinhDavid K Chalmers
Apr 28, 2012·Bioinformatics·Adrià Cereto-MassaguéSantiago Garcia-Vallvé
May 17, 2012·Journal of Chemical Information and Modeling·John J IrwinRyan G Coleman
Aug 8, 2012·Acta Crystallographica. Section D, Biological Crystallography·Rita AzevedoArthur Oubrie
Aug 18, 2012·Journal of Medicinal Chemistry·Kathrin E MartzStefan A Laufer
Dec 25, 2012·Current Pharmaceutical Design·Preethi Badrinarayan, G Narahari Sastry
Feb 16, 2013·Current Medicinal Chemistry·Luca SancinetoOriana Tabarrini
Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
Jun 12, 2013·PLoS Computational Biology·Drew H BryantLydia E Kavraki
Jun 29, 2013·Journal of Computer-aided Molecular Design·Matthias WirthWolfgang H B Sauer
Jul 12, 2013·Chembiochem : a European Journal of Chemical Biology·Gerd NielsenHarald Schwalbe
Aug 15, 2013·Journal of Medicinal Chemistry·Oscar P J van LindenChris de Graaf
Aug 21, 2013·Journal of Chemical Information and Modeling·Maria Letizia BarrecaVioletta Cecchetti
Jul 23, 2014·Journal of Medicinal Chemistry·Ye HuJürgen Bajorath
Sep 19, 2014·Journal of Chemical Information and Modeling·Sheng TianTingjun Hou

❮ Previous
Next ❯

Citations

Aug 14, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Dorota KrasowskaLuca Sancineto
Feb 2, 2021·European Journal of Medicinal Chemistry·Moustafa M MadkourMohammed I El-Gamal

❮ Previous
Next ❯

Methods Mentioned

BETA
NMR
X-ray

Software Mentioned

DecoyFinder
Nlobe
LigPrep
Protein Preparation Wizard
All
Glide
Schrödinger
AS
SiteMap
Schrödinger Maestro interface

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.