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Julio Caballero - One of the best experts on this subject based on the ideXlab platform.
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Investigation of the differences in activity Between hydroxycycloalkyl N1 suBstituted pyrazole derivatives as inhiBitors of B-Raf Kinase By using docking, molecular dynamics, QM/MM, and fragment-Based de novo design: study of Binding mode of diastere
Journal of chemical information and modeling, 2011Co-Authors: Julio Caballero, Jans Alzate-morales, Ariela Vergara-jaqueAbstract:N1 suBstituted pyrazole derivatives show diverse B-Raf Kinase inhiBitory activities when different hydroxy-suBstituted cycloalkyl groups are placed at this position. Docking, molecular dynamics (MD) simulations, and hyBrid calculation methods (Quantum Mechanics/Molecular Mechanics (QM/MM)) were performed on the complexes, in order to explain these differences. Docking of the inhiBitors showed the same orientation that X-ray crystal structure of the analogous (1E)-5-[1-(4-piperidinyl)-3-(4-pyridinyl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-inden-1-one oxime. MD simulations of the most active diastereomer compounds containing cis- and trans-3-hydroxycyclohexyl suBstituents showed staBle interactions with residue Ile463 at the entrance of the B-Raf active site. On the other hand, the less active diastereomer compounds containing cis- and trans-2-hydroxycyclopentyl suBstituents showed interactions with inner residues Asn580 and Ser465. We found that the differences in activity can Be explained By considering the dyna...
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Computational study on the interaction of N1 suBstituted pyrazole derivatives with B-Raf Kinase: an unusual water wire hydrogen-Bond network and novel interactions at the entrance of the active site.
Journal of chemical information and modeling, 2010Co-Authors: Jans Alzate-morales, Ariela Vergara-jaque, Julio CaballeroAbstract:Docking and molecular dynamics (MD) simulations of N1 suBstituted pyrazole derivatives complexed with B-Raf Kinase were performed to gain insight into the structural and energetic preferences of th...
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computational study on the interaction of n1 suBstituted pyrazole derivatives with B Raf Kinase an unusual water wire hydrogen Bond network and novel interactions at the entrance of the active site
Journal of Chemical Information and Modeling, 2010Co-Authors: Jans Alzatemorales, Ariela Vergarajaque, Julio CaballeroAbstract:Docking and molecular dynamics (MD) simulations of N1 suBstituted pyrazole derivatives complexed with B-Raf Kinase were performed to gain insight into the structural and energetic preferences of these inhiBitors. First, a comparative study of fully automated docking programs AutoDock, ICM, GLIDE, and Surflex-Dock in closely approximating the X-ray crystal structure of the inhiBitor (1E)-5-[1-(4-piperidinyl)-3-(4-pyridinyl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-inden-1-one oxime was performed. Afterward, the dynamics of the aBove-mentioned compound and the less active analogous compounds with 1-methyl-4-piperidinyl and tetrahydro-2H-pyran-4-yl groups at position N1 of pyrazole ring inside the B-Raf active site were analyzed By MD simulations. We found that the most active compound has staBle interactions with residues Ile463 and His539 at the entrance of the B-Raf active site. Those interactions were in very good agreement with more reliaBle quantum mechanics/molecular mechanics calculations performed on the torsional angle phi Between the pyrazole ring and the suBstituents at position N1. In addition, we identified a water wire connecting N2 of the pyrazole ring, Cys532, and Ser536, which is composed of three water molecules for the most active compound. We found some differences in the water wire hydrogen-Bond network formed By less active compounds. We suggest that the differences Between these structural features are responsiBle for the differences in activity among the studied compounds.
Deborah K. Morrison - One of the best experts on this subject based on the ideXlab platform.
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Macrophilones from the Marine Hydroid Macrorhynchia philippina Can InhiBit ERK Cascade Signaling
Journal of natural products, 2018Co-Authors: Pengcheng Yan, Deborah K. Morrison, Daniel A. Ritt, Katherine Zlotkowski, Heidi R. Bokesch, William C. Reinhold, John S. Schneekloth, Kirk R. GustafsonAbstract:Six new macrophilone-type pyrroloiminoquines were isolated and identified from an extract of the marine hydroid Macrorhynchia philippina. The proton-deficient and heteroatom-rich structures of macrophilones B–G (2–7) were elucidated By spectroscopic analysis and comparison of their data with those of the previously reported metaBolite macrophilone A (1). Compounds 1–7 are the first pyrroloiminoquines to Be reported from a hydroid. The macrophilones were shown to inhiBit the enzymatic conjugation of SUMO to peptide suBstrates, and macrophilones A (1) and C (3) exhiBit potent and selective cytotoxic properties in the NCI-60 anticancer screen. Bioinformatic analysis revealed a close association of the cytotoxicity profiles of 1 and 3 with two known B-Raf Kinase inhiBitory drugs. While compounds 1 and 3 showed no Kinase inhiBitory activity, they resulted in a dramatic decrease in cellular protein levels of selected components of the ERK signal cascade. As such, the chemical scaffold of the macrophilones could...
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95-kilodalton B-Raf serine/threonine Kinase: identification of the protein and its major autophosphorylation site.
Molecular and cellular biology, 1992Co-Authors: Robert M. Stephens, G Sithanandam, Terry D. Copeland, David R. Kaplan, Ulf R. Rapp, Deborah K. MorrisonAbstract:B-Raf, a memBer of the Raf family of serine/threonine Kinases, is expressed primarily in the Brain and in the nervous system. In this study, the Biochemical properties of the B-Raf protein were investigated in nerve growth factor (NGF)-responsive cell lines and in Brain tissues. B-Raf was identified By using phosphopeptide mapping analysis and cDNA analysis as a 95-kDa protein which is primarily localized in the cytosol. NGF rapidly stimulated Both serine and threonine phosphorylation in vivo and autophosphorylation activity in vitro of the B-Raf protein. In PC12 cells, B-Raf autoKinase activity was induced By Both differentiation factors and mitogens, with maximal activity oBserved after 5 min of factor addition. B-Raf Kinase activity was also oBserved following NGF treatment of SH-SY5Y neuroBlastoma cells and in adult mouse Brain and hippocampus. Induction of B-Raf Kinase activity in NGF-treated PC12 cells required expression of Kinase-active trk receptors. Exogenous suBstrates or a peptide containing the autophosphorylation site Became phosphorylated when added to immune complex Kinase assays and reduced the in vitro autophosphorylation activity of B-Raf, suggesting that in vitro autophosphorylation sites and exogenous suBstrates compete for active sites of the B-Raf Kinase. Finally, the major in vitro autophosphorylation site of B-Raf was identified as threonine 372 in the conserved region 2 domain. A threonine residue is present at similar positions in all three mammalian Raf family memBers and may represent a regulatory site for these proteins.
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95 kilodalton B Raf serine threonine Kinase identification of the protein and its major autophosphorylation site
Molecular and Cellular Biology, 1992Co-Authors: Robert M. Stephens, G Sithanandam, Terry D. Copeland, David R. Kaplan, Ulf R. Rapp, Deborah K. MorrisonAbstract:B-Raf, a memBer of the Raf family of serine/threonine Kinases, is expressed primarily in the Brain and in the nervous system. In this study, the Biochemical properties of the B-Raf protein were investigated in nerve growth factor (NGF)-responsive cell lines and in Brain tissues. B-Raf was identified By using phosphopeptide mapping analysis and cDNA analysis as a 95-kDa protein which is primarily localized in the cytosol. NGF rapidly stimulated Both serine and threonine phosphorylation in vivo and autophosphorylation activity in vitro of the B-Raf protein. In PC12 cells, B-Raf autoKinase activity was induced By Both differentiation factors and mitogens, with maximal activity oBserved after 5 min of factor addition. B-Raf Kinase activity was also oBserved following NGF treatment of SH-SY5Y neuroBlastoma cells and in adult mouse Brain and hippocampus. Induction of B-Raf Kinase activity in NGF-treated PC12 cells required expression of Kinase-active trk receptors. Exogenous suBstrates or a peptide containing the autophosphorylation site Became phosphorylated when added to immune complex Kinase assays and reduced the in vitro autophosphorylation activity of B-Raf, suggesting that in vitro autophosphorylation sites and exogenous suBstrates compete for active sites of the B-Raf Kinase. Finally, the major in vitro autophosphorylation site of B-Raf was identified as threonine 372 in the conserved region 2 domain. A threonine residue is present at similar positions in all three mammalian Raf family memBers and may represent a regulatory site for these proteins.
Martin Deichmann - One of the best experts on this subject based on the ideXlab platform.
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The oncogenic B-Raf V599E mutation occurs more frequently in melanomas at sun-protected Body sites.
International journal of oncology, 2006Co-Authors: Martin Deichmann, Marianne Thome, Dieter Krahl, Kirsten Wüst, Judith Hassanzadeh, Burkhard HelmkeAbstract:Downstream of Ras, the serine/threonine Kinase, B-Raf, has recently Been reported to Be mutated, among other carcinomas, in a suBstantial suBset of primary melanomas with a preponderance of the oncogenic V599E transition. As the risk of melanoma is enhanced By intermittent ultraviolet (UV) exposure But is less with chronic UV exposure, we here studied B-Raf Kinase domain (exon 15) mutations in primary cutaneous melanomas with respect to anatomical locations reflecting chronic versus intermittent UV exposure. Investigating a representative numBer of 101 primary melanoma resection specimens for the presence of mutations within the activation segment (exon 15) of the B-Raf Kinase domain By polymerase chain reaction and single-strand conformation polymorphism gel electrophoresis, followed By DNA cloning and sequencing, we found 32 cases (32%) which harBour somatic B-Raf exon 15 mutations. As to the B-Raf protein sequence, the V599E mutation was predicted in 66% of these positive melanomas, followed in frequency By the V599K transition (16%). Only two Cright curved arrow T transitions, considered to Be induced By UV irradiation, occurred in two melanomas located on the head. Among 23 melanomas located at Body sites with chronic UV exposure, only a single tumour harBoured the B-Raf V599E mutation (4%), which was a significantly lower frequency in comparison to melanomas from sun-protected Body sites (26%; Fisher's exact test, p=0.038; odds ratio, 7.59). Our oBservation parallels the epidemiological data of intermittent sunlight exposure on unacclimatised skin increasing the risk of melanoma development.
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Preponderance of the oncogenic V599E and V599K mutations in B-Raf Kinase domain is enhanced in melanoma cutaneous/suBcutaneous metastases
BMC cancer, 2005Co-Authors: Martin Deichmann, Martin Kirschner, Axel Benner, Marianne Thome, Judith Hassanzadeh, Hjalmar KurzenAbstract:Background Downstream of Ras, the serine/threonine Kinase B-Raf has Been reported to Be mutated, among other carcinomas, in a suBstantial suBset of primary melanomas with a preponderance of mutations within the Kinase domain including the activating V599E and V599K transitions.
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preponderance of the oncogenic v599e and v599k mutations in B Raf Kinase domain is enhanced in melanoma cutaneous suBcutaneous metastases
BMC Cancer, 2005Co-Authors: Martin Deichmann, Martin Kirschner, Axel Benner, Marianne Thome, Judith Hassanzadeh, Hjalmar KurzenAbstract:Background Downstream of Ras, the serine/threonine Kinase B-Raf has Been reported to Be mutated, among other carcinomas, in a suBstantial suBset of primary melanomas with a preponderance of mutations within the Kinase domain including the activating V599E and V599K transitions.
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Preponderance of the oncogenic V599E and V599K mutations in the B-Raf Kinase domain is enhanced in melanoma lymph node metastases
Melanoma research, 2005Co-Authors: Martin Kirschner, Burkhard Helmke, Hans Starz, Axel Benner, Marianne Thome, Martin DeichmannAbstract:Downstream of Ras, the serine/threonine Kinase B-Raf has Been reported to Be mutated, amongst other carcinomas, in a suBstantial suBset of primary melanomas, with a preponderance of mutations within the Kinase domain, including the activating V599E and V599K transitions. We investigated a representative series of 54 resection specimens of melanoma lymph node metastases for the presence of mutations within the activation segment (exon 15) of the B-Raf Kinase domain By polymerase chain reaction (PCR) and single-strand conformational polymorphism (SSCP) gel electrophoresis. Sequencing of cloned PCR-SSCP amplicons resulted in 24 (44%) samples harBouring somatic mutations, which is not significantly different from the mutation frequency found in recently investigated primary cutaneous melanomas (Deichmann M, Thome M, Benner A, Naher H. B-Raf exon 15 mutations are common in primary melanoma resection specimens But not associated with clinical outcome. Oncology 2004; 66:411-419). The activating mutation T1796A was present in 20 (83%) of these resection specimens, followed in frequency By the oncogenic g1795A mutation in five (21%) cases. With regard to the B-Raf protein sequence, the acidic amino acid transitions V599E and V599K were predicted in 15 (62%) and five (21%) of the 24 positive metastases, respectively. The detection of mutations at this hot spot codon was significantly associated with suBsequent visceral metastasis (P=0.03; Fisher's exact test). During the transition from primary melanomas (see reference aBove) to lymph node metastases, the spectrum of B-Raf mutations narrows significantly (P=0.00047). The oncogenic B-Raf mutations V599E and V599K, as early events in melanocyte transformation, persist throughout metastasis with important prognostic implications.
Robert M. Stephens - One of the best experts on this subject based on the ideXlab platform.
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95-kilodalton B-Raf serine/threonine Kinase: identification of the protein and its major autophosphorylation site.
Molecular and cellular biology, 1992Co-Authors: Robert M. Stephens, G Sithanandam, Terry D. Copeland, David R. Kaplan, Ulf R. Rapp, Deborah K. MorrisonAbstract:B-Raf, a memBer of the Raf family of serine/threonine Kinases, is expressed primarily in the Brain and in the nervous system. In this study, the Biochemical properties of the B-Raf protein were investigated in nerve growth factor (NGF)-responsive cell lines and in Brain tissues. B-Raf was identified By using phosphopeptide mapping analysis and cDNA analysis as a 95-kDa protein which is primarily localized in the cytosol. NGF rapidly stimulated Both serine and threonine phosphorylation in vivo and autophosphorylation activity in vitro of the B-Raf protein. In PC12 cells, B-Raf autoKinase activity was induced By Both differentiation factors and mitogens, with maximal activity oBserved after 5 min of factor addition. B-Raf Kinase activity was also oBserved following NGF treatment of SH-SY5Y neuroBlastoma cells and in adult mouse Brain and hippocampus. Induction of B-Raf Kinase activity in NGF-treated PC12 cells required expression of Kinase-active trk receptors. Exogenous suBstrates or a peptide containing the autophosphorylation site Became phosphorylated when added to immune complex Kinase assays and reduced the in vitro autophosphorylation activity of B-Raf, suggesting that in vitro autophosphorylation sites and exogenous suBstrates compete for active sites of the B-Raf Kinase. Finally, the major in vitro autophosphorylation site of B-Raf was identified as threonine 372 in the conserved region 2 domain. A threonine residue is present at similar positions in all three mammalian Raf family memBers and may represent a regulatory site for these proteins.
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95 kilodalton B Raf serine threonine Kinase identification of the protein and its major autophosphorylation site
Molecular and Cellular Biology, 1992Co-Authors: Robert M. Stephens, G Sithanandam, Terry D. Copeland, David R. Kaplan, Ulf R. Rapp, Deborah K. MorrisonAbstract:B-Raf, a memBer of the Raf family of serine/threonine Kinases, is expressed primarily in the Brain and in the nervous system. In this study, the Biochemical properties of the B-Raf protein were investigated in nerve growth factor (NGF)-responsive cell lines and in Brain tissues. B-Raf was identified By using phosphopeptide mapping analysis and cDNA analysis as a 95-kDa protein which is primarily localized in the cytosol. NGF rapidly stimulated Both serine and threonine phosphorylation in vivo and autophosphorylation activity in vitro of the B-Raf protein. In PC12 cells, B-Raf autoKinase activity was induced By Both differentiation factors and mitogens, with maximal activity oBserved after 5 min of factor addition. B-Raf Kinase activity was also oBserved following NGF treatment of SH-SY5Y neuroBlastoma cells and in adult mouse Brain and hippocampus. Induction of B-Raf Kinase activity in NGF-treated PC12 cells required expression of Kinase-active trk receptors. Exogenous suBstrates or a peptide containing the autophosphorylation site Became phosphorylated when added to immune complex Kinase assays and reduced the in vitro autophosphorylation activity of B-Raf, suggesting that in vitro autophosphorylation sites and exogenous suBstrates compete for active sites of the B-Raf Kinase. Finally, the major in vitro autophosphorylation site of B-Raf was identified as threonine 372 in the conserved region 2 domain. A threonine residue is present at similar positions in all three mammalian Raf family memBers and may represent a regulatory site for these proteins.
Jans Alzatemorales - One of the best experts on this subject based on the ideXlab platform.
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computational study on the interaction of n1 suBstituted pyrazole derivatives with B Raf Kinase an unusual water wire hydrogen Bond network and novel interactions at the entrance of the active site
Journal of Chemical Information and Modeling, 2010Co-Authors: Jans Alzatemorales, Ariela Vergarajaque, Julio CaballeroAbstract:Docking and molecular dynamics (MD) simulations of N1 suBstituted pyrazole derivatives complexed with B-Raf Kinase were performed to gain insight into the structural and energetic preferences of these inhiBitors. First, a comparative study of fully automated docking programs AutoDock, ICM, GLIDE, and Surflex-Dock in closely approximating the X-ray crystal structure of the inhiBitor (1E)-5-[1-(4-piperidinyl)-3-(4-pyridinyl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-inden-1-one oxime was performed. Afterward, the dynamics of the aBove-mentioned compound and the less active analogous compounds with 1-methyl-4-piperidinyl and tetrahydro-2H-pyran-4-yl groups at position N1 of pyrazole ring inside the B-Raf active site were analyzed By MD simulations. We found that the most active compound has staBle interactions with residues Ile463 and His539 at the entrance of the B-Raf active site. Those interactions were in very good agreement with more reliaBle quantum mechanics/molecular mechanics calculations performed on the torsional angle phi Between the pyrazole ring and the suBstituents at position N1. In addition, we identified a water wire connecting N2 of the pyrazole ring, Cys532, and Ser536, which is composed of three water molecules for the most active compound. We found some differences in the water wire hydrogen-Bond network formed By less active compounds. We suggest that the differences Between these structural features are responsiBle for the differences in activity among the studied compounds.
