ABSTRACT Title of Dissertation: ENERGETICS OF DRUG INTERACTIONS
... compensation where changes in the binding enthalpies are compensated by changes in the binding entropies. In drug binding to the more flexible p38α MAP kinase mutants, a single-point C→S mutation distal from the binding site, changes the interaction between the N- and C-terminal structural domains o ...
... compensation where changes in the binding enthalpies are compensated by changes in the binding entropies. In drug binding to the more flexible p38α MAP kinase mutants, a single-point C→S mutation distal from the binding site, changes the interaction between the N- and C-terminal structural domains o ...
Synopsis of Some Recent Tactical Application of Bioisosteres in
... for the mechanism-based HCV NS3 protease inhibitor telaprevir (12).39 The (S)-R-ketoamide in 12 readily racemizes at higher pH and, most notably, in human plasma to afford the(R)diastereomer, which exhibits 30-fold weaker biological activity (Figure 2). The (R)-diastereomer of 12 is the primary meta ...
... for the mechanism-based HCV NS3 protease inhibitor telaprevir (12).39 The (S)-R-ketoamide in 12 readily racemizes at higher pH and, most notably, in human plasma to afford the(R)diastereomer, which exhibits 30-fold weaker biological activity (Figure 2). The (R)-diastereomer of 12 is the primary meta ...
Characterization of Two Pharmacophores on the Multidrug
... Pascaud et al., 1998; Wang et al., 2000) all led to the same conclusion of several different specific sites on P-glycoprotein. However, the number of sites, their chemical selectivities, and their mutual relationships remain unclear. The molecular mechanism underlying the “multispecific” recognition ...
... Pascaud et al., 1998; Wang et al., 2000) all led to the same conclusion of several different specific sites on P-glycoprotein. However, the number of sites, their chemical selectivities, and their mutual relationships remain unclear. The molecular mechanism underlying the “multispecific” recognition ...
Selective inhibitor of LRRK2, a protein kinase
... unique because a missense mutation, G2019S, is frequently found in not only familial but also sporadic PD cases4,5. The most common and extensively characterized mutation, G2019S, enhances kinase activity, suggesting that small molecule LRRK2 kinase inhibitors may serve as potential therapeutic age ...
... unique because a missense mutation, G2019S, is frequently found in not only familial but also sporadic PD cases4,5. The most common and extensively characterized mutation, G2019S, enhances kinase activity, suggesting that small molecule LRRK2 kinase inhibitors may serve as potential therapeutic age ...
Macrocycles in new drug discovery
... Conformational restriction, including cycliza tion of drug-like molecules, is commonly used to improve potency towards a target [31] . To successfully bind to a protein, a molecule has to adopt a bioactive conformation, and by limit ing the number of conformations available to the unbound molecule ...
... Conformational restriction, including cycliza tion of drug-like molecules, is commonly used to improve potency towards a target [31] . To successfully bind to a protein, a molecule has to adopt a bioactive conformation, and by limit ing the number of conformations available to the unbound molecule ...
Is there a role for EGFR Tyrosine Kinase Inhibitors in recurrent
... Cohort A will include 32 patients at first recurrence with EGFRVIII mutations. Cohort B will include 32 patients at first recurrence with EGFR gene amplification but no EGFRVIII mutation ...
... Cohort A will include 32 patients at first recurrence with EGFRVIII mutations. Cohort B will include 32 patients at first recurrence with EGFR gene amplification but no EGFRVIII mutation ...
Mechanisms of ibrutinib resistance
... • Ibrutinib targets in vivo CLL proliferation through inhibition of B-cell receptor signaling activity • BTKC481S confers resistance to ibrutinib as a consequence of loss of irreversible drug binding • PLCg2 mutations confers resistance to ibrutinib via re-activation of BCR-signaling • Overcome ibru ...
... • Ibrutinib targets in vivo CLL proliferation through inhibition of B-cell receptor signaling activity • BTKC481S confers resistance to ibrutinib as a consequence of loss of irreversible drug binding • PLCg2 mutations confers resistance to ibrutinib via re-activation of BCR-signaling • Overcome ibru ...
Structural Basis for Interaction of Inhibitors with Cyclin
... interest in chemical CDKs inhibitors that could play an important role in the discovery of a new family of antitumor agents [12]. Since ATP is the authentic cofactor of CDK2 it can be considered as a "lead compound" for discovery of CDK2 inhibitors. However, there are two major concerns: adenine con ...
... interest in chemical CDKs inhibitors that could play an important role in the discovery of a new family of antitumor agents [12]. Since ATP is the authentic cofactor of CDK2 it can be considered as a "lead compound" for discovery of CDK2 inhibitors. However, there are two major concerns: adenine con ...
Anaplastic lymphoma kinase (ALK) - Blue Ridge Institute for Medical
... more fully characterized in 1997. Physiological ALK participates in embryonic nervous system development, but its expression decreases after birth. ALK is a member of the insulin receptor superfamily and is most closely related to leukocyte tyrosine kinase (Ltk), which is a receptor protein-tyrosine ...
... more fully characterized in 1997. Physiological ALK participates in embryonic nervous system development, but its expression decreases after birth. ALK is a member of the insulin receptor superfamily and is most closely related to leukocyte tyrosine kinase (Ltk), which is a receptor protein-tyrosine ...
Advances in Lung Cancer 2016: a year in review
... Initial results of the second generation ALK/ROS1 kinase inhibitor ceritinib (750 mg once daily) ...
... Initial results of the second generation ALK/ROS1 kinase inhibitor ceritinib (750 mg once daily) ...
Australian Public Assessment Report for Dasatinib Proprietary Product Name: Sprycel
... developed in three stages. First, a base model was developed to estimate the effect of dasatinib steady state average concentration (Cavg.ss) on cCCyR. Second, a full model was developed to incorporate the effect of covariates. Third, the final model was developed by eliminating covariates that were ...
... developed in three stages. First, a base model was developed to estimate the effect of dasatinib steady state average concentration (Cavg.ss) on cCCyR. Second, a full model was developed to incorporate the effect of covariates. Third, the final model was developed by eliminating covariates that were ...
Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase
... eliminate xenobiotics, such as drugs. In the drug discovery and development arena, it is important to identify metabolic pathways and key enzymes involved in drug clearance, as metabolites produced by different enzymatic pathways may possess different activity or toxicity profiles. With the increasi ...
... eliminate xenobiotics, such as drugs. In the drug discovery and development arena, it is important to identify metabolic pathways and key enzymes involved in drug clearance, as metabolites produced by different enzymatic pathways may possess different activity or toxicity profiles. With the increasi ...
The challenge of selecting protein kinase assays
... Protein kinases play an integral role in many cell signaling pathways and comprise one of the largest families of homologous proteins, with ∼ 518 members in the human kinome [1]. As such, protein kinases represent the largest ‘druggable’ gene family within the human genome [2]. Overexpression and/or ...
... Protein kinases play an integral role in many cell signaling pathways and comprise one of the largest families of homologous proteins, with ∼ 518 members in the human kinome [1]. As such, protein kinases represent the largest ‘druggable’ gene family within the human genome [2]. Overexpression and/or ...
Antimicrobial Drug Use and Resistance among Respiratory
... the resistance trait in the absence of antibiotic selective pressure. Because most newly arising mutations are neutral or deleterious, it has been argued that the mutation rate has evolved to be as low as possible. However, not all mutations are deleterious. Mutations may be beneficial for the micro ...
... the resistance trait in the absence of antibiotic selective pressure. Because most newly arising mutations are neutral or deleterious, it has been argued that the mutation rate has evolved to be as low as possible. However, not all mutations are deleterious. Mutations may be beneficial for the micro ...
... approaches, protein sequence is represented by a feature vector xi, with 20 binary bits (one for each type of amino acid) for each sequence position as its components. Samples of resistance and non-resistance mutations are used for training a statistical learning system to derive the classifiers and ...
The poster sessions are an important highlight of these conferences
... Abstract: DS is a multi-targeted TKI of BCR ABL and SRC w. significant activity in pts with CML CP resistant or intolerant of IM. Phase II trial to study efficacy and safety of DS in pts with previously untreated CML CP Methods: Preliminary objective was to estimate the proportion of pts attaining ...
... Abstract: DS is a multi-targeted TKI of BCR ABL and SRC w. significant activity in pts with CML CP resistant or intolerant of IM. Phase II trial to study efficacy and safety of DS in pts with previously untreated CML CP Methods: Preliminary objective was to estimate the proportion of pts attaining ...
SCIENTIFIC DISCUSSION 1. Introduction
... Chronic myelogenous leukaemia (CML) is one of several chronic myeloproliferative diseases, a family of clonal disorders of pluripotential hematopoetic stem cells in the marrow. CML has a yearly incidence of 1 in 100 000 in Western countries and its frequency increases steadily with age (Greer JP 200 ...
... Chronic myelogenous leukaemia (CML) is one of several chronic myeloproliferative diseases, a family of clonal disorders of pluripotential hematopoetic stem cells in the marrow. CML has a yearly incidence of 1 in 100 000 in Western countries and its frequency increases steadily with age (Greer JP 200 ...
Inhibitors of transglutaminase 2: A therapeutic option in
... pathological functions, catalyzes the transamidation and deamidation of glutamine residues in peptides. Amongst others, the enzyme is involved in the pathogenesis of celiac disease, a T-cell mediated inflammatory disorder of the small intestine. Here, gluten peptides are the environmental factors re ...
... pathological functions, catalyzes the transamidation and deamidation of glutamine residues in peptides. Amongst others, the enzyme is involved in the pathogenesis of celiac disease, a T-cell mediated inflammatory disorder of the small intestine. Here, gluten peptides are the environmental factors re ...
A new family of covalent inhibitors block nucleotide binding to the
... further, whereby LmPYK activity was monitored over time in the presence of 50 μM DBS (Figure 1e). Maximal inhibition of ∼ 80 % was achieved after ∼ 250 min (Figure 1e, curve A), although LmPYK inhibition never reached 100 % inhibition even after 10 h (after prolonged incubation periods at 25 ◦ C bot ...
... further, whereby LmPYK activity was monitored over time in the presence of 50 μM DBS (Figure 1e). Maximal inhibition of ∼ 80 % was achieved after ∼ 250 min (Figure 1e, curve A), although LmPYK inhibition never reached 100 % inhibition even after 10 h (after prolonged incubation periods at 25 ◦ C bot ...
Fragment-Based Discovery of the Pyrazol-4
... ring to adopt a partly twisted conformation relative to the plane of the pyrazole-benzimidazole scaffold. Further optimization was aimed at improving the affinity for both Aurora kinases and increasing cellular potency. Considering the physicochemical properties of 10 (MW ) 417, clogP ) 3.7 and 4 HB ...
... ring to adopt a partly twisted conformation relative to the plane of the pyrazole-benzimidazole scaffold. Further optimization was aimed at improving the affinity for both Aurora kinases and increasing cellular potency. Considering the physicochemical properties of 10 (MW ) 417, clogP ) 3.7 and 4 HB ...
(12)Indian Patent Application ______________________________________________________________
... provide an effective therapeutic treatment in immune-mediated diseases, e.g. intestinal disorders, such as autoimmune and inflammatory diseases or conditions. T lymphocyte (T cell) infiltration into the small intestine and colon has been linked specifically to the pathogenesis of Coeliac diseases, f ...
... provide an effective therapeutic treatment in immune-mediated diseases, e.g. intestinal disorders, such as autoimmune and inflammatory diseases or conditions. T lymphocyte (T cell) infiltration into the small intestine and colon has been linked specifically to the pathogenesis of Coeliac diseases, f ...
Drug Delivery and Drug Resistance: EGFR
... important in the sense of focusing on tumor cells instead of normal cells to minimize the side effects. Furthermore, the tyrosine kinase inhibitors, gefitinib and erlotinib, are more effective in tumor cells harbouring specific mutations, such as the deletion mutations in exon 19 or different point ...
... important in the sense of focusing on tumor cells instead of normal cells to minimize the side effects. Furthermore, the tyrosine kinase inhibitors, gefitinib and erlotinib, are more effective in tumor cells harbouring specific mutations, such as the deletion mutations in exon 19 or different point ...
An Integrated Chemical Biology Approach Identifies Specific
... inhibition of IGFR, CD99, or MGST1 (10–13). However, so far none of these approaches has received clinical approval. Protein kinases have received significant attention over the past decade because many of these play important roles, for example, in cancer and can be readily engaged by small molecul ...
... inhibition of IGFR, CD99, or MGST1 (10–13). However, so far none of these approaches has received clinical approval. Protein kinases have received significant attention over the past decade because many of these play important roles, for example, in cancer and can be readily engaged by small molecul ...