alexa Identification Of Multivalent Ligands Of Human Farnesyl Pyrophosphate Synthase And Tipping The Affinity Balance Towards Allosteric Binding
ISSN: 2161-0444

Medicinal Chemistry
Open Access

Like us on:
OMICS International organises 3000+ Global Conferenceseries Events every year across USA, Europe & Asia with support from 1000 more scientific Societies and Publishes 700+ Open Access Journals which contains over 50000 eminent personalities, reputed scientists as editorial board members.

Open Access Journals gaining more Readers and Citations

700 Journals and 15,000,000 Readers Each Journal is getting 25,000+ Readers

This Readership is 10 times more when compared to other Subscription Journals (Source: Google Analytics)

Share This Page

Additional Info

Loading Please wait..

3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing
December 08-10, 2014 DoubleTree by Hilton Hotel San Francisco Airport, USA

Jaeok Park, Chun Yuen Leung, Joris W De Schutter, Michael Sebag, Judes Poirier, Youla S Tsantrizos and Albert M Berghuis
Accepted Abstracts: Med Chem
DOI: 10.4172/2161-0444.S1.013
Human farnesyl pyrophosphate synthase (hFPPS) produces farnesyl pyrophosphate, an isoprenoid required for a variety of cellular processes including protein prenylation. Inhibition of hFPPS, and thus of prenylation of small GTPases, has been well established as the mechanism of action of the nitrogen-containing bisphosphonate (N-BP) drugs, currently best known for their anti-bone resorptive benefits. Inhibition of hFPPS also produces anticancer effects: N-BPs have shown to inhibit motility and viability of tumor cells and act in synergy with other anticancer agents both in vitro and in vivo. Furthermore, is implicated in Alzheimer?s disease (AD). Through analysis of polymorphisms in the hFPPS gene and mRNA levels in autopsyconfirmed subjects, we have established a genetic link between hFPPS overexpression and elevated levels of phosphorylated tau (P-Tau) in the human brain, the latter of which is a cellular hallmark of AD progression. The physicochemical properties of the current N-BP drugs, however, compromise their full pharmacological potential as hFPPS inhibiting agents. They have poor membrane permeability and extremely high affinity to bone, and thus their clinical usefulness is limited mainly to the treatment of osteoporosis and bone cancer metastasis. The poor drug-like properties of N-BPs are due to their highly charged bisphosphonate moiety, which mimics the pyrophosphate of hFPPS substrates, dimethylallyl pyrophosphate (DMAPP) and geranyl pyrophosphate (GPP). N-BPs bind to the DMAPP/GPP sub-pocket of hFPPS via Mg2+-mediated interactions between their bisphosphonate moiety and two aspartate-rich motifs of the enzyme. Using a multistage screening method employing differential scanning fluorimetry, NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we have identified bisphosphonate compounds with dual binding modes: they bind to the enzyme?s active site in the presence of Mg2+, but also to a nearby allosteric inhibitory pocket in the absence of the metal ion. Furthermore, by removing a phosphonate group from the bisphosphonate moiety we have created monophosphonate inhibitors that bind exclusively to the allosteric pocket even in the presence of Mg2+. Alternatively, modification of the side chain scaffold of the lead compounds has resulted in bisphosphonates that also bind only to the allosteric pocket. Further optimization of these compounds may lead to development of non-bisphosphonate human therapeutics for non-skeletal cancers and taupathy-associated neurodegeneration.
image PDF   |   image HTML
Peer Reviewed Journals
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

1-702-714-7001Extn: 9037

Business & Management Journals


1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

1-702-714-7001 Extn: 9042

© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version