Morelloflavone as a novel inhibitor of mitotic kinesin Eg5

Journal of Biochemistry
Tomisin Happy OgunwaTakayuki Miyanishi

Abstract

Among 40 plant-derived biflavonoids with inhibitory potential against Eg5, morelloflavone from Garcinia dulcis leaves was selected for further testing based on in silico analysis of binding modes, molecular interactions, binding energies and functional groups that interact with Eg5. Computational models predicted that morelloflavone binds the putative allosteric pocket of Eg5, within the cavity surrounded by amino acid residues of Ile-136, Glu-116, Glu-118, Trp-127, Gly-117, Ala-133, Glu-215, Leu-214 and Tyr-211. Binding energy was -8.4 kcal/mol, with a single hydrogen bond formed between morelloflavone and Tyr-211. The binding configuration was comparable to that of a reference inhibitor, S-trityl-L-cysteine. Subsequent biochemical analysis in vitro confirmed that morelloflavone inhibited both the basal and microtubule-activated ATPase activity of Eg5 in a manner that does not compete with ATP binding. Morelloflavone also suppressed Eg5 gliding along microtubules. These results suggest that morelloflavone binds the allosteric binding site in Eg5 and thereby inhibits ATPase activity and motor function of Eg5.

References

Nov 7, 1998·Antiviral Research·D E ZembowerB E Korba
Aug 31, 2000·Annual Review of Biochemistry·D A Compton
Sep 27, 2002·Chemistry & Biology·Zoltan MaligaTimothy J Mitchison
Dec 28, 2002·Journal of Natural Products·Xing-Cong LiRonald L Cihlar
Mar 6, 2003·Chemistry & Biology·Junko NakazawaHiroyuki Osada
Dec 16, 2003·Journal of Molecular Biology·Youwei YanLawrence C Kuo
Jul 13, 2004·The Journal of Biological Chemistry·Jared C CochranSusan P Gilbert
Jan 25, 2005·The Journal of Biological Chemistry·Jared C CochranSusan P Gilbert
Jan 25, 2005·Bioscience, Biotechnology, and Biochemistry·Toshiya MasudaShigetomo Yonemori
Aug 4, 2006·Journal of Medicinal Chemistry·Khalilah G ReddieTimothy M Dore
Jul 7, 2007·Natural Product Research·Nongporn Hutadilok-TowatanaWilawan Mahabusarakam
Feb 23, 2008·Biochemistry·Latesh LadRoman Sakowicz
Apr 15, 2008·Archives of Pharmacal Research·Hyun Pyo KimSam Sik Kang
Oct 2, 2009·The Biochemical Journal·Hung Yi Kristal KaanFrank Kozielski
Mar 23, 2010·Cell Cycle·Carolyn A Moores
Mar 30, 2010·Journal of Agricultural and Food Chemistry·Hui YangEdward J Kennelly
Apr 20, 2010·Journal of Computer-aided Molecular Design·Daniel Seeliger, Bert L de Groot
Jun 5, 2010·Journal of Medicinal Chemistry·Shinya OishiNobutaka Fujii
Jan 18, 2012·Journal of Medicinal Chemistry·Fang WangFrank Kozielski
Jul 25, 2012·Nature Reviews. Cancer·Oliver Rath, Frank Kozielski
Sep 21, 2012·Acta Crystallographica. Section D, Biological Crystallography·S K TalapatraF Kozielski
Oct 11, 2012·Ayu·Chandrakant KatiyarShefali Katiyar
Feb 5, 2013·Journal of Advanced Pharmaceutical Technology & Research·Ciddi Veeresham
Feb 23, 2013·Biochimica Et Biophysica Acta·Gordon M Cragg, David J Newman
Feb 26, 2013·European Journal of Medicinal Chemistry·Hala Bakr El-Nassan
May 8, 2013·Chemical & Pharmaceutical Bulletin·Tetsuro ItoMunekazu Iinuma
Jul 6, 2014·Chemico-biological Interactions·Jaime Andrés PereañezEdison Osorio
Dec 6, 2014·TheScientificWorldJournal·Elisha SoloweyHaya Lorberboum-Galski
Feb 11, 2015·Computational Biology and Chemistry·Olaposi I Omotuyi, Hiroshi Ueda
Feb 10, 2016·Frontiers in Pharmacology·Bhaswati ChoudhuryJibon Kotoky
Mar 16, 2016·Future Medicinal Chemistry·Stephanie M Myers, Ian Collins
Nov 9, 2016·Mini Reviews in Medicinal Chemistry·Vanessa Silva GontijoClaudio Viegas
Feb 18, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sheng YuSam Fong Yau Li
Feb 24, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hong YaoXinhua Lin

❮ Previous
Next ❯

Citations

Apr 19, 2019·Pharmaceuticals·Tomisin Happy OgunwaTakayuki Miyanishi
Mar 6, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·José C J M D S Menezes, Marc F Diederich

❮ 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.