Exploring the lapse in druggability: Sequence Analysis, Structural Dynamics and binding site characterization of K-RasG12C variant, a feasible oncotherapeutics target

Anti-cancer Agents in Medicinal Chemistry
Emmanuel Adefemi AdenijiMahmoud Soliman

Abstract

The difficulty in druggability has presented a hurdle in the treatment of cancer diseases associated with dysfunctional mutant K-ras. This has so far impeded the emergence of suitable inhibitors to discontinue its aberrant activities. Despite the identification of different interactive sites, limited information exists in literature about their characteristics that could aid the design and development of appropriate inhibitors that could bind at its catalytic or effector binding sites, thereby disrupting oncogenic activities. While binding of inhibitors at the K-ras catalytic site could alter activity switch, targeting effector binding regions would disrupt its association with effector proteins such as Raf. Moreover, identification and cross validation of druggable sites on mutant K-ras coupled with characterization would aid the design of characteristic chemical compounds for such sites. Herein, we carried out a comprehensive study of K-ras G12C mutant to identify, cross-validate and characterize its binding sites for potential druggability, coupled with the elucidation of alterations in 3D conformations and dynamics. From our results, the identified druggable sites were selected based on cross-validation and were characteriz...Continue Reading

References

Apr 1, 1996·Current Opinion in Cell Biology·C J Marshall
Mar 31, 2000·Trends in Cell Biology·J M ShieldsC J Der
Jan 2, 2003·Nature Reviews. Cancer·Julian Downward
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Nov 18, 2005·Methods : a Companion to Methods in Enzymology·John F Hancock, Ian A Prior
Mar 27, 2007·Chemical Biology & Drug Design·Tom Halgren
May 13, 2009·Journal of Chemical Information and Modeling·Thomas A Halgren
Oct 6, 2009·Trends in Biochemical Sciences·Gloria Fuentes, Alfonso Valencia
Aug 6, 2010·Drug Discovery Today·Stéphanie PérotBruno O Villoutreix
Sep 15, 2010·PLoS Computational Biology·Suryani LukmanJ Andrew McCammon
Oct 19, 2010·Nucleic Acids Research·Simon A ForbesP Andrew Futreal
Sep 29, 2011·Journal of Molecular Biology·Greg BuhrmanCarla Mattos
Nov 3, 2011·PloS One·Barry J GrantAlemayehu A Gorfe
Dec 6, 2011·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Anathe O M PatschullBibek Gooptu
Aug 18, 2012·Blood·Ashley F WardKevin M Shannon
Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
Aug 29, 2013·Carcinogenesis·Anne M J GilsingMatty P Weijenberg
Sep 26, 2013·Methods in Molecular Biology·Charles C David, Donald J Jacobs
Mar 20, 2014·Cancer Biology & Therapy·Joanna H M TongKa Fai To
Apr 8, 2014·Journal of Chemical Information and Modeling·E Seifert
Oct 18, 2014·Nature Reviews. Drug Discovery·Adrienne D CoxChanning J Der
Feb 19, 2015·The New England Journal of Medicine·Sandra M SwainUNKNOWN CLEOPATRA Study Group
May 6, 2015·Seminars in Cancer Biology·Ramzi M MohammadAsfar S Azmi
Jun 2, 2015·The New England Journal of Medicine·James LarkinJedd D Wolchok
Jun 4, 2015·Molecular Cancer Research : MCR·John C HunterKenneth D Westover
Aug 12, 2015·Seminars in Cancer Biology·Anupam Bishayee, Keith Block
Jul 9, 2013·Journal of Chemical Theory and Computation·Daniel R Roe, Thomas E Cheatham
Nov 23, 2015·Seminars in Cancer Biology·Keith I BlockMassimo Zollo
Jan 28, 2016·Chemical Reviews·Shaoyong LuJian Zhang
Mar 11, 2016·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Frank McCormick
Apr 14, 2016·Current Topics in Medicinal Chemistry·Xiaokai LiJason E Gestwicki
Aug 11, 2016·Drug Discovery Today·Candice Y Wilson, Peter Tolias

❮ 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.