The Experts below are selected from a list of 277440 Experts worldwide ranked by ideXlab platform
Herbert Waldmann - One of the best experts on this subject based on the ideXlab platform.
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protein structure similarity clustering and natural product structure as guiding principles in drug discovery
Drug Discovery Today, 2005Co-Authors: Marcus A Koch, Herbert WaldmannAbstract:The identification of new chemical entities that are capable of altering protein function lies at the heart of the hit and lead finding process, for which combinatorial chemistry has emerged as a powerful tool. Following the maturation of combinatorial chemistry and compound Library Development, it was soon recognized that biological relevance, design and diversity of a Library are more important than Library size. The universe of conceivable compounds is almost infinite, therefore, the decisive question arises: where is a biologically validated starting point in structural space from which to build a compound Library to be found? As a new approach to address this complex problem, a synergistic strategy is presented, which is based on protein structure similarity clustering and natural product structure as guiding rationales.
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compound Library Development guided by protein structure similarity clustering and natural product structure
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Marcus A Koch, Larsoliver Wittenberg, Duraiswamy A Jeyaraj, Eleni Gourzoulidou, Kerstin Reinecke, Sudipta Basu, Alex Odermatt, Herbert WaldmannAbstract:To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound Library Development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11β-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2–3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.
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Development of natural product derived receptor tyrosine kinase inhibitors based on conservation of protein domain fold
Journal of Medicinal Chemistry, 2003Co-Authors: Lars Kissau, Petra Stahl, Ralph Mazitschek, Athannasios Giannis, Herbert WaldmannAbstract:Receptor tyrosine kinases (RTKs) such as Tie-2, IGF1R, Her-2/Neu, EGFR, and VEGFR1-3 play crucial roles in the control of cell growth and differentiation. Inhibition of such RTKs has become a major focus of current anticancer drug Development, and therefore the discovery of new classes of inhibitors for these signal-transducing proteins is of prime importance. We have recently proposed a novel concept for improving the hit-finding process by employing natural products as biologically validated starting points in structural space for compound Library Development. In this concept, natural products are regarded as evolutionary chosen ligands for protein domains which are structurally conserved yet genetically mobile. Here we report on the discovery of novel and highly selective VEGFR-2 and -3, Tie-2, and IGF1R inhibitors derived from the naturally occurring Her-2/Neu kinase inhibitor nakijiquinone C and developed on the basis of this concept. Based on the structure of the natural product, a small Library (74...
Marcus A Koch - One of the best experts on this subject based on the ideXlab platform.
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protein structure similarity clustering and natural product structure as guiding principles in drug discovery
Drug Discovery Today, 2005Co-Authors: Marcus A Koch, Herbert WaldmannAbstract:The identification of new chemical entities that are capable of altering protein function lies at the heart of the hit and lead finding process, for which combinatorial chemistry has emerged as a powerful tool. Following the maturation of combinatorial chemistry and compound Library Development, it was soon recognized that biological relevance, design and diversity of a Library are more important than Library size. The universe of conceivable compounds is almost infinite, therefore, the decisive question arises: where is a biologically validated starting point in structural space from which to build a compound Library to be found? As a new approach to address this complex problem, a synergistic strategy is presented, which is based on protein structure similarity clustering and natural product structure as guiding rationales.
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compound Library Development guided by protein structure similarity clustering and natural product structure
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Marcus A Koch, Larsoliver Wittenberg, Duraiswamy A Jeyaraj, Eleni Gourzoulidou, Kerstin Reinecke, Sudipta Basu, Alex Odermatt, Herbert WaldmannAbstract:To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound Library Development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11β-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2–3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.
Mohamed, Nor Aini - One of the best experts on this subject based on the ideXlab platform.
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Understanding the reading habit and attitudes among the rural community in low literacy rate areas in Malaysia: rural Library perspectives
'Emerald', 2020Co-Authors: Samsuddin, Samsul Farid, Mohamed Shaffril, Hayrol Azril, Bolong Jusang, Mohamed, Nor AiniAbstract:Purpose: The purpose of this paper is to investigate the reading habit and attitude among rural communities in the low literacy rate areas in Malaysia. Design/methodology/approach: Multi-stage cluster and simple random sampling were employed and 400 respondents who live nearby the rural Library were selected. Findings: Moderate levels of reading attitude were obtained from the result of the study, in which several variables produced a significant relationship in the reading attitude (education level, household income and time spent in reading). Practical implications: Better understanding on the reading habit and attitude among rural communities could produce better information on the service provision towards the establishment of rural libraries in low literacy rate areas in Malaysia. This would also increase the utilisation of reading sources and services provided. Originality/value: The paper provides better understanding on the reading habit and attitude among the rural communities in the low literacy rate areas in using the facilities provided by the rural libraries. The findings may be useful to the rural literacy and Library Development community in the developing countries
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Understanding the reading habit and attitudes among the rural community in low literacy rate areas in Malaysia
'Emerald', 2020Co-Authors: Samsuddin, Samsul Farid, Mohamed Shaffril, Hayrol Azril, Bolong Jusang, Mohamed, Nor AiniAbstract:Purpose: The purpose of this paper is to investigate the reading habit and attitude among rural communities in the low literacy rate areas in Malaysia. Design/methodology/approach: Multi-stage cluster and simple random sampling were employed and 400 respondents who live nearby the rural Library were selected. Findings: Moderate levels of reading attitude were obtained from the result of the study, in which several variables produced a significant relationship in the reading attitude (education level, household income and time spent in reading). Practical implications: Better understanding on the reading habit and attitude among rural communities could produce better information on the service provision towards the establishment of rural libraries in low literacy rate areas in Malaysia. This would also increase the utilisation of reading sources and services provided. Originality/value: The paper provides better understanding on the reading habit and attitude among the rural communities in the low literacy rate areas in using the facilities provided by the rural libraries. The findings may be useful to the rural literacy and Library Development community in the developing countries. © 2019, Emerald Publishing Limited
Ricardo L E Furlan - One of the best experts on this subject based on the ideXlab platform.
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chemically engineered extracts as an alternative source of bioactive natural product like compounds
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Silvia N Lopez, Ayelen I Ramallo, Manuel Gonzalez Sierra, Susana Zacchino, Ricardo L E FurlanAbstract:The access to libraries of molecules with interesting biomolecular properties is a limiting step in the drug discovery process. By virtue of a long molecular evolution process, natural products are recognized as biologically validated starting points in structural space for Library Development. We introduce here a strategy to generate natural product-like libraries. A semisynthetic mixture of compounds was produced by diversification of a natural product extract through the chemical transformation of common chemical functionalities in natural products into chemical functionalities rarely found in nature. The resulting mixture showed antifungal activity against Candida albicans, whereas the starting extract did not show such activity. Bioguided fractionation led to the isolation of a previously undescribed active semisynthetic pyrazole. The result illustrates how biological activity can be generated by designed chemical diversification of a natural product mixture, and represents the proof of principle of an alternative strategy for producing natural product-like libraries from natural products libraries.
Jiyong Hong - One of the best experts on this subject based on the ideXlab platform.
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role of natural product diversity in chemical biology
Current Opinion in Chemical Biology, 2011Co-Authors: Jiyong HongAbstract:Through the natural selection process, natural products possess a unique and vast chemical diversity and have been evolved for optimal interactions with biological macromolecules. Owing to their diversity, target affinity, and specificity, natural products have demonstrated enormous potential as modulators of biomolecular function, been an essential source for drug discovery, and provided design principles for combinatorial Library Development.