Computational sampling of a cryptic drug binding site in a protein receptor: explicit solvent molecular dynamics and inhibitor docking to p38 MAP kinase

Journal of Molecular Biology
Tamara Frembgen-Kesner, Adrian H Elcock

Abstract

An increasing number of structural studies reveal alternative binding sites in protein receptors that become apparent only when an inhibitor binds, and correct prediction of these situations presents a significant challenge to computer-aided drug design efforts. A striking example is provided by recent crystal structures of the p38 MAP kinase, where a 10A movement of the Phe169 side-chain creates a new binding site adjacent to the ATP binding site that is exploited by the diaryl urea inhibitor BIRB796. Here, we show that this binding site can be successfully and repeatedly identified in explicit-solvent molecular dynamics (MD) simulations of the protein that begin from an unliganded p38 crystal structure. Ligand-docking calculations performed on 5000 different structural snapshots generated during MD indicate that the conformations sampled are often surprisingly competent to bind the inhibitor BIRB796 in the crystallographically correct position and with docked energies that are generally more favorable than those of other positions. Similar docking studies with an ATP-binding site-directed inhibitor suggest that it may be possible to develop hybrid inhibitors that target both the ATP and cryptic binding sites simultaneously. I...Continue Reading

References

Dec 1, 1994·Protein Science : a Publication of the Protein Society·E G Hutchinson, J M Thornton
Oct 1, 1998·Structure·Z WangE J Goldsmith
Mar 1, 1985·Physical Review A: General Physics·W G Hoover
Sep 24, 1999·Protein Science : a Publication of the Protein Society·M YoungS Highsmith
Jun 8, 2000·Journal of Medicinal Chemistry·H A CarlsonJ A McCammon
Jun 8, 2001·Proteins·D J JacobsM F Thorpe
Mar 16, 2002·Nature Structural Biology·Christopher PargellisJohn Regan
May 23, 2002·Cell·Morgan Huse, John Kuriyan
Aug 23, 2002·Pharmacology & Therapeutics·Richard A Engh, Dirk Bossemeyer
Feb 8, 2003·Annual Review of Biophysics and Biomolecular Structure·Natasja Brooijmans, Irwin D Kuntz
Apr 3, 2003·Journal of the American Chemical Society·Bruce G SzczepankiewiczMichael R Jirousek
Jul 3, 2003·Nature Reviews. Drug Discovery·Simon J Teague
Sep 3, 2003·Nature Reviews. Drug Discovery·Sanjay KumarJohn C Lee
Oct 17, 2003·Journal of Medicinal Chemistry·Alejandra TrejoDavid M Goldstein
Feb 18, 2004·Biophysical Chemistry·Kaihsu Tai
Mar 20, 2004·Science·Martin E M NobleLouise N Johnson
Mar 24, 2004·Current Opinion in Chemical Biology·Susan Jones, Janet M Thornton
Mar 24, 2004·Journal of Molecular Biology·James R Horn, Brian K Shoichet
Apr 10, 2004·Journal of Computer-aided Molecular Design·Badry D BursulayaCharles L Brooks
Apr 22, 2004·Journal of Molecular Graphics & Modelling·Viktor Hornak, Carlos Simmerling
Jul 23, 2004·The Journal of Chemical Physics·Donald HamelbergJ Andrew McCammon
Jul 24, 2004·Acta Crystallographica. Section D, Biological Crystallography·Alexander W Schüttelkopf, Daan M F van Aalten
Aug 3, 2004·Nature Biotechnology·Antonio MacchiaruloJanet M Thornton
Oct 9, 2004·Journal of Computational Chemistry·Rie TatsumiHaruki Nakamura
Nov 16, 2004·Nature Structural & Molecular Biology·Jeffrey F OhrenCharles A Hasemann
Dec 8, 2004·Current Opinion in Structural Biology·Jeanne A Hardy, James A Wells
Feb 16, 2005·Nature Biotechnology·Miles A FabianDavid J Lockhart
Feb 23, 2005·Current Pharmaceutical Design·Venkatraman MohanRenee L DesJarlais
Apr 30, 1998·The Journal of Physical Chemistry. B·A D MacKerellM Karplus

❮ Previous
Next ❯

Citations

Jan 16, 2008·Journal of Computer-aided Molecular Design·Rommie E AmaroJ Andrew McCammon
Feb 7, 2008·Journal of Computer-aided Molecular Design·Shashidhar RaoRamy Farid
Jun 18, 2009·Journal of Computer-aided Molecular Design·Lars NeumannDoris Hafenbradl
May 10, 2012·Quarterly Reviews of Biophysics·Katrina W Lexa, Heather A Carlson
Jan 11, 2012·Journal of Chemical Information and Modeling·Matteo ChioccioliPaola Gratteri
Apr 30, 2013·Journal of Chemical Information and Modeling·Daria B KokhRebecca C Wade
May 31, 2008·Journal of Chemical Information and Modeling·Christophe Guilbert, Thomas L James
Jul 4, 2012·Proceedings of the National Academy of Sciences of the United States of America·Gregory R Bowman, Phillip L Geissler
Apr 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Yibing ShanDavid E Shaw
May 17, 2011·Physical Biology·Zhe ZhangEmil Alexov
Oct 29, 2011·BMC Bioinformatics·Samuel C Flores, Mark B Gerstein
Oct 1, 2014·BMC Bioinformatics·William R PittTom L Blundell
Feb 10, 2012·Current Pharmaceutical Design·Michael J SchniedersPengyu Ren
Sep 1, 2006·Expert Opinion on Drug Discovery·Xavier Barril, Xavier Fradera
Mar 3, 2015·Proceedings of the National Academy of Sciences of the United States of America·Gregory R BowmanSusan Marqusee
Jan 14, 2012·Journal of Medicinal Chemistry·David J HugginsBruce Tidor
Sep 2, 2014·Journal of Chemical Information and Modeling·Alessio AtzoriRichard A Bryce
Jul 16, 2008·Bioorganic & Medicinal Chemistry·Deliang ChenCatherine H Schein
Nov 13, 2007·Biochimica Et Biophysica Acta·Chung F Wong
Aug 20, 2008·Journal of Computational Chemistry·Zunnan Huang, Chung F Wong
Aug 27, 2010·Proteins·Guilherme Menegon Arantes
Sep 12, 2009·Journal of Molecular Recognition : JMR·Stefan HenrichRebecca C Wade
Feb 18, 2016·IEEE/ACM Transactions on Computational Biology and Bioinformatics·Preethi RanganarayananVigneshwar Ramakrishnan
Apr 8, 2016·Future Medicinal Chemistry·Samia Aci-SèchePascal Bonnet
Dec 18, 2014·In Silico Pharmacology·Pramod C Nair, John O Miners
Apr 14, 2016·Chemical Reviews·Jeffrey R WagnerRommie E Amaro
Aug 21, 2010·Bioorganic & Medicinal Chemistry·Federico FilomiaM Cristina Menziani
Jul 17, 2009·Structure·Dariya S GlazerRuss B Altman
Jun 26, 2013·Chemistry & Biology·Sanjay B HariDustin J Maly
Dec 5, 2013·Evidence-based Complementary and Alternative Medicine : ECAM·Yan WangDavid Chi-Cheong Wan
Jul 12, 2016·Journal of Chemical Theory and Computation·Daria B KokhRebecca C Wade

❮ Previous
Next ❯

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.