The use of small molecular fragments as the source of bioactivity is a common practice in Medicinal Chemistry. Illustrative examples can be mentioned of famous fragment-sized drugs for common therapeutic applications, with aspirin and paracetamol emerging above all; as well as of techniques, which are available to date for assisting with enduring reliability a fragment-based conception of medicaments. Also, efforts are unrelentingly ongoing in reducing the complexity of natural metabolites with remarkable biology into smaller, fragment-like entities, either by traditional structure-based techniques or by means of sophisticated bioinformatics-aided deconvolution methods. In spite of the apparent impasse of the current research in Medicinal Chemistry, the shift of the focus to fragment-sized molecules that is implied in Chemical Genetics and omics approaches has renewed a tremendous interest for the biological potential of these entities, especially in view of their inherent propensity in addressing a wide spectrum of biological targets. In this arena, the systematic exploration of fragments through structural alternatives which might serve as isosteres and/or isofunctional alternatives is strategic in assisting the study of equivalents with defined pharmacological profile, and the availability of practical methods towards this scope would offer new opportunities in the Medicinal Chemistry underlying both Fragment-Based Drug Design and the search for fragment-sized drugs. With these principles in mind, a contribution for tackling these issues was sought, which enables a practical and efficient appreciation of molecular mimicry by relying on the ability of Principal Component Analysis in reducing the multitude of physicochemical bi- and tridimensional features of libraries with over 10,000 fragment-sized chemicals (MW < 300). A visual representation of the progression of molecular dissimilarity results from the analysis, from which countless applications in Medicinal Chemistry, as well as Material Chemistry and Organic Synthesis might sprout. As a proof of the mimicry principle, seven highly varied classes of small hydrophilic molecules were identified and chosen through this similarity enabling solution, which displayed an SPR binding profile towards heterogeneous proteins comparable to that of a natural benzoquinone fragment selected as a query. Note. Part of this work will be described in the PhD thesis of Sofie Knutsson, Department of Chemistry, Umeå University. References 1. Natural-Product-Derived Fragments for Fragment-Based Ligand Discovery. Over, B.; Wetzel, S.; Grütter, C.; Nakai, Y.; Renner, S.; Rauh, D. Waldmann, H. Nature Chemistry, 2013, 5, 21-28. 2. Molecular Similarity in Medicinal Chemistry. Maggiora, G.; Vogt, M.; Stumpfe, D.; Bajorath, J. J. Med. Chem. 2014, 57, 3186-3204. For an application of PCA in the evaluation of similarity trends with classes of compounds, see: Principal Components Describing Biological Activities and Molecular Diversity of Heterocyclic Aromatic Ring Fragments. Gibson, S.; McGuire, R.; Rees, D. C. J. Med. Chem. 1996, 39, 4065-4072. 3. Drug Repurposing through Non-Hypothesis Driven Phenotypic Screening. Reaume, A. G. Drug Discov. Today: Ther. Strategies 2011, 8, 85-88.
Isosteres and Other Isofunctional Alternatives by Multivariated Analysis of Molecular Fragments
Luciana Auzzas;
2014
Abstract
The use of small molecular fragments as the source of bioactivity is a common practice in Medicinal Chemistry. Illustrative examples can be mentioned of famous fragment-sized drugs for common therapeutic applications, with aspirin and paracetamol emerging above all; as well as of techniques, which are available to date for assisting with enduring reliability a fragment-based conception of medicaments. Also, efforts are unrelentingly ongoing in reducing the complexity of natural metabolites with remarkable biology into smaller, fragment-like entities, either by traditional structure-based techniques or by means of sophisticated bioinformatics-aided deconvolution methods. In spite of the apparent impasse of the current research in Medicinal Chemistry, the shift of the focus to fragment-sized molecules that is implied in Chemical Genetics and omics approaches has renewed a tremendous interest for the biological potential of these entities, especially in view of their inherent propensity in addressing a wide spectrum of biological targets. In this arena, the systematic exploration of fragments through structural alternatives which might serve as isosteres and/or isofunctional alternatives is strategic in assisting the study of equivalents with defined pharmacological profile, and the availability of practical methods towards this scope would offer new opportunities in the Medicinal Chemistry underlying both Fragment-Based Drug Design and the search for fragment-sized drugs. With these principles in mind, a contribution for tackling these issues was sought, which enables a practical and efficient appreciation of molecular mimicry by relying on the ability of Principal Component Analysis in reducing the multitude of physicochemical bi- and tridimensional features of libraries with over 10,000 fragment-sized chemicals (MW < 300). A visual representation of the progression of molecular dissimilarity results from the analysis, from which countless applications in Medicinal Chemistry, as well as Material Chemistry and Organic Synthesis might sprout. As a proof of the mimicry principle, seven highly varied classes of small hydrophilic molecules were identified and chosen through this similarity enabling solution, which displayed an SPR binding profile towards heterogeneous proteins comparable to that of a natural benzoquinone fragment selected as a query. Note. Part of this work will be described in the PhD thesis of Sofie Knutsson, Department of Chemistry, Umeå University. References 1. Natural-Product-Derived Fragments for Fragment-Based Ligand Discovery. Over, B.; Wetzel, S.; Grütter, C.; Nakai, Y.; Renner, S.; Rauh, D. Waldmann, H. Nature Chemistry, 2013, 5, 21-28. 2. Molecular Similarity in Medicinal Chemistry. Maggiora, G.; Vogt, M.; Stumpfe, D.; Bajorath, J. J. Med. Chem. 2014, 57, 3186-3204. For an application of PCA in the evaluation of similarity trends with classes of compounds, see: Principal Components Describing Biological Activities and Molecular Diversity of Heterocyclic Aromatic Ring Fragments. Gibson, S.; McGuire, R.; Rees, D. C. J. Med. Chem. 1996, 39, 4065-4072. 3. Drug Repurposing through Non-Hypothesis Driven Phenotypic Screening. Reaume, A. G. Drug Discov. Today: Ther. Strategies 2011, 8, 85-88.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
