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T B Ng – One of the best experts on this subject based on the ideXlab platform.

Olof P Karlsson – One of the best experts on this subject based on the ideXlab platform.

  • kinetic studies of small molecule interactions with protein kinases using biosensor technology
    Analytical Biochemistry, 2005
    Co-Authors: Helena Nordin, Maria Jungnelius, Robert Karlsson, Olof P Karlsson

    Protein kinases are among the most commonly targeted groups of molecules in drug discovery today. Despite this, there are few examples of using surface plasmon resonance (SPR) for kinase Inhibitor interaction studies, probably reflecting the need for better developed assays for these proteins. In this article, we present a general methodology that uses biosensor technology to study small molecule binding to eight different serine/threonine and tyrosine kinases. Mild immobilization conditions and a carefully composed assay buffer were identified as key success factors. The methodology package consists of direct binding studies of compounds to immobilized kinases, kinase activity assays to confirm Inhibitory effects, detailed kinetic analyses of Inhibitor binding, and competition assays with ATP for identification of competitive Inhibitors. The kinetic assays resolve affinity into the rates of Inhibitor binding and dissociation. Therefore, more detailed information on the relation between Inhibitor structure and function is obtained. This might be of key importance for the development of effective kinase Inhibitors.

Dongdong Sun – One of the best experts on this subject based on the ideXlab platform.

  • Rational creation and systematic analysis of cervical cancer kinase–Inhibitor binding profile
    Journal of Computer-Aided Molecular Design, 2019
    Co-Authors: Min Han, Dongdong Sun

    The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase Inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule Inhibitors should generally exhibit high promiscuity and broad specificity across the hCC-related kinase array, it is supposed that the established kinase targets of hCC can be targeted unexpectedly by certain noncognate kinase Inhibitors. This provides a novel idea to practice the new uses for old drugs in anti-cancer chemotherapy. Here, we create a systematic kinase–Inhibitor binding profile in a high-throughput manner by molecular docking and consensus scoring, where the kinases have been collected as therapeutic targets of hCC and the Inhibitors are reversible, ATP-competitive and readily available. The docking/scoring scheme is tested rigorously with structure-solved and affinity-known kinase–Inhibitor complex samples, which is later demonstrated to be effective in inferring unexpected Inhibitor response to hCC-related kinases. Few promising kinase–Inhibitor pairs are identified from the profile and tested experimentally at cellular and molecular levels. It is found that the kinase–Inhibitor promiscuity is a common phenomenon but only few can interaction effectively and inhibit potently. In addition, the high-scoring Inhibitors generally exhibit good suppressing potency on hCC cell viability as compared to those low-scoring ones, imparting that the created profile can well reflect the tumor cytotoxicity of noncognate kinase Inhibitors. A further kinase assay suggests that the ErbB family kinases are the potential targets of these high-scoring Inhibitors, with noncognate Inhibitory activity up to nanomolar level. Structure analysis reveals that the nonbonded interactions of potent noncogante kinase–Inhibitor binding can divided into a polar tail and a nonpolar lobe, which confer specificity and stability to the binding, respectively.

Jianhong Li – One of the best experts on this subject based on the ideXlab platform.

  • a spider araneus ventricosus chymotrypsin Inhibitor that acts as an elastase Inhibitor and a microbial serine protease Inhibitor
    Comparative Biochemistry and Physiology B, 2013
    Co-Authors: Miao Yuan, Sha Zhan, Jianhong Li

    Spider-derived Kunitz-type serine protease Inhibitors have been shown to exhibit plasmin and elastase inhibition activity and potassium channel blocking activity, but thus far, no additional roles for spider-derived chymotrypsin Inhibitors have been elucidated. In this study, a spider (Araneus ventricosus) chymotrypsin Inhibitor (AvCI) that acts as an elastase Inhibitor and a microbial serine protease Inhibitor was identified. AvCI is a 70-amino acid mature peptide that displays eight conserved cysteine residues and a P1 lysine residue. Recombinant AvCI expressed in baculovirus-infected insect cells demonstrated Inhibitory activity against chymotrypsin (Ki 49.85 nM), but not trypsin, which defines a role for AvCI as a spider-derived chymotrypsin Inhibitor. AvCI also exhibited Inhibitory activity against microbial serine proteases such as subtilisin A (Ki 20.51 nM) and proteinase K (Ki 65.42 nM). Furthermore, AvCI exhibited no detectable Inhibitory effects on factor Xa, thrombin, tissue plasminogen activator, or plasmin; however, AvCI strongly inhibited human neutrophil elastase (Ki 8.74 nM) and porcine pancreatic elastase (Ki 11.32 nM), indicating that AvCI acts as an anti-elastolytic factor. These findings constitute molecular evidence that AvCI acts as an Inhibitor against chymotrypsin, microbial serine proteases, and elastases. This paper provides a novel view of the functions of a spider-derived chymotrypsin Inhibitor.

S. Leelamma – One of the best experts on this subject based on the ideXlab platform.

  • Enzyme Inhibitors in tuber crops and their thermal stability
    Plant Foods for Human Nutrition, 1995
    Co-Authors: S. Prathibha, Bala Nambisan, S. Leelamma

    Tubers of Cassava ( Manihot esculenta ), yams ( Dioscorea esculenta ), aroids ( Amorphophallus campanulatus, Colocasia esculenta, Xanthosoma sagittifolium ) and Coleus ( Solenostemon rotundifolius ) were screened for Inhibitory activities against amylase, trypsin and chymotrypsin. Coleus tuber possessed the highest anti-amylase activity, whereas Colocasia tuber was the most potent source of anti-tryptic and anti-chymotryptic activity. Xanthosoma tubers exhibited amylase Inhibitory activity and Amorphophallus tubers antiprotease activity. Dioscorea esculenta had low levels of amylase and chymotrypsin Inhibitors, while Cassava tubers were totally free of Inhibitors. When tubers were processed by pressure cooking, there was significant reduction/complete elimination in Inhibitory activity. Partial retention of inhibition was observed in the case of amylase Inhibitor in Dioscorea, chymotrypsin Inhibitor in Colocasia and trypsin Inhibitor in Colocasia, Coleus and Amorphophallus. In vitro experiments on heat stability of the different Inhibitors revealed almost similar pattern of inactivation.