Structural feature study of benzofuran derivatives as farnesyltransferase inhibitors

Moorthy, N. S. Hari Narayana; Sousa, Sérgio F.; Ramos, María J.; Fernandes, Pedro A.

doi:10.3109/14756366.2011.552885

Journal of Enzyme Inhibition and Medicinal Chemistry

2011

DOI: 10.3109/14756366.2011.552885

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Structural feature study of benzofuran derivatives as farnesyltransferase inhibitors

N. S. Hari Narayana Moorthy

Sérgio F. Sousa

María J. Ramos

et al.

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Cited by 19 publications

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References 65 publications

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“…Ras proteins are a small guanine nucleotide-hydrolyzing proteins that play important roles in cell growth and spread in the mitogen-activated protein kinase (MAPK) signaling pathway [1]. Ras is the most mutated gene that is involved in almost one-third of all cancers [2, 3].…”

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confidence: 99%

Arresting kinase suppressor of Ras in an inactive state

Badshah

Mabkhot

2017

Chin J Cancer

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Ras protein signaling pathways are important in controlling the plight of different types of cancer. Here we discussed the paper entitled “Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling” published in Nature journal on inactivating the kinase suppressor of Ras (KSR) protein using a small molecule as an inhibitor by Dhawan et al. A biphenyl ether analogue of a quinazoline binds in one of the binding pockets of KSR and results in stabilization of its inactive state. In this inactive state, KSR is unable to take part in the cascade of protein association to perform the signalling process.

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mentioning

confidence: 99%

Arresting kinase suppressor of Ras in an inactive state

Badshah

Mabkhot

2017

Chin J Cancer

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Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

et al. 2016

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Molecular dynamics analysis of a series of 22 potential farnesyltransferase substrates containing a CaaX-motif

et al. 2012

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Protein farnesyltransferase (FTase) is an important target in many research fields, more markedly so in cancer investigation since several proteins known to be involved in human cancer development are thought to serve as substrates for FTase and to require farnesylation for proper biological activity. Several FTase inhibitors (FTIs) have advanced into clinical testing. Nevertheless, despite the progress in the field several functional and mechanistic doubts on the FTase catalytic activity have persisted. This work provides some crucial information on this important enzyme by describing the application of molecular dynamics simulations using specifically designed molecular mechanical parameters for a variety of 22 CaaX peptides known to work as natural substrates or inhibitors for this enzyme. The study involves a comparative analysis of several important molecular aspects, at the mechanistic level, of the behavior of substrates and inhibitors at the dynamic level, including the behavior of the enzyme and peptides, as well as their interaction, together with the effect of the solvent. Properties evaluated include the radial distribution function of the water molecules around the catalytically important zinc metal atom and cysteine sulfur of CaaX, the conformations of the substrate and inhibitor and the corresponding RMSF values, critical hydrogen bonds, and several catalytically relevant distances. These results are discussed in light of recent experimental and computational evidence that provides new insights into the activity of this enzyme.

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Structural feature study of benzofuran derivatives as farnesyltransferase inhibitors

Cited by 19 publications

References 65 publications

Arresting kinase suppressor of Ras in an inactive state

Arresting kinase suppressor of Ras in an inactive state

Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Molecular dynamics analysis of a series of 22 potential farnesyltransferase substrates containing a CaaX-motif

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