Drug Discovery Today: Technologies
Vol. 10, No. 4 2013
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Approaches to Scaffold Hopping David G. Lloyd University of South Australia, Adelaide SA5000, Australia. Email: ([email protected])
Since the coining of the phrase ‘Scaffold Hopping’ in 1999 – by Gisbert Schneider, one of this issue’s contributors – there have been approximately 200 papers indexed in PubMed which reference or espouse this particular approach to molecular design. These papers encompass and span traditional medicinal chemical, structureinformed, pharmacophore-informed and de novo methodologies with a common objective in all cases to ‘hop’ or move from one molecular structure to a pharmacologically equivalent or superior alternative. There is of course some room for interpretation at an individual level of what exactly a scaffold is, or how far we may move in terms of molecular (dis)similarity to as to be deemed a legitimate ‘hop’ and not simple molecular modification. Alongside the absence of precise definition, the motivation for hopping is myriad – to drive novelty or potency or to move away from potential toxicity or ADME issues or even just simply to challenge the established wisdom prevailing for a given target. Regardless of why it is being done, the end game in any of these approaches should be such that the diversity of liganding exhibited by targets of interest is expanded beyond our initial knowledge or expectation and new scaffolds are advanced with elegant demonstration of rationale and endeavour. Scaffold hops should serve to furnish us with new beacons of activity in previously uncharted chemical space, and map unexplored ligand territory. If done well, these scaffold hops provide diverse and novel compounds which beget additional understanding and research opportunity – or better still meet unmet need with improved profiles in targets relevant to human disease. From my perspective, the very best hops are ones which throw out new branches on the chemical phylogenetic tree for a target, where the move from ‘established’ chemotype to novel agent is one which makes you look twice, and forces the inner chemist to stop and think how could these two compounds (which on the page appear so very different) have equivalent molecular pharmacology. Being forced to stop and think every once in a while is a good thing. 1740-6749/$ ß 2013 Elsevier Ltd. All rights reserved.
This issue of ‘Drug Discovery Today: Technologies’ takes a wide-angle look at Scaffold Hopping through a series of targeted reviews. It is intended to serve both as an introduction to those unfamiliar with the topic, but we also hope it will also give you occasion to pause for thought as we present some of the diverse methodologies. In our six papers we explore different approaches to move from a known active to a structurally distinct novel active. These approaches are presented in the context of their application to various drug design challenges. Our first paper, fittingly, comes from the progenitor of Scaffold Hopping, Gisbert Schneider and covers the use of de novo computational design for Scaffold Hopping. De novo design has significantly advanced from its earliest incarnation wherein scaffolds suggested where often so structurally novel as to be synthetically impossible to produce – which was often spun as ‘idea generators’ to the point where synthetic accessibility, fragment replacement and many other mainstays of the synthetic organic or medicinal chemist are hard coded to the software. Schneider discusses both structure- and ligand-based de novo Scaffold Hopping through examples of their application and highlights areas for future research to further refine the state of the art. David G. Lloyd PhD is the Vice-Chancellor and President of the University of South Australia. He is concurrently Professor of Computer-Aided Drug Design in the University’s Division of Health Sciences. Before his appointment in UniSA in 2013, he was a Professor in the School of Biochemistry and Immunology in Trinity College Dublin, Ireland, where he headed the Molecular Design Group. His research has focused on the development of novel active ligands for targets of biological relevance through the application of computational methodology, driving novelty not only in the ligands themselves but also in the approaches used for the discovery of the ligands. He holds a BSc and PhD from Dublin City University.
http://dx.doi.org/10.1016/j.ddtec.2013.09.001
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Drug Discovery Today: Technologies |
The construction of targeted screening libraries continues to furnish novel compounds, hits and leads for pharmaceutical discovery. The molecular diversity of such libraries is a principle concern – ensuring sufficient diversity within a desired pharmacological target window is not straightforward. In their contribution, Sheppard, MacRitchie and Roberts Spearing detail the application of Scaffold Hopping as a key component in their new approach to library design. They detail the combination of iterative structure-based docking and molecular replacement – to furnish a diverse and enhanced set of core scaffold considerations which can be used to furnish screening libraries targeted to specific gene family members. Another major challenge is explored in our third article by Darren Fayne, targeting the inhibition of protein–protein interactions (PPIs) through scaffold hops from big to small molecules. In highlighting the advances in and application of specific computational techniques to tackle PPI inhibitor design, this review explores the issue from to standpoints – can we determine if a given PPI is druggable through computational analysis and if so, what approaches can be taken for depeptidisation and peptidomimetic design – through exploration of specific examples of success in this field. The application of analysis of topology for the exploration of molecular similarity and dissimilarity is explored in the article from Galvez, Galvez-Llompart, Zanni and GarciaDomenech. The authors outline the concept of molecular topology from its origins in mathematical graph theory through to its applications in Scaffold Hopping for the
e452
www.drugdiscoverytoday.com
Vol. 10, No. 4 2013
classification and identification of not only pharmacoequivalent compounds with diverse structures, but also the prediction of non-equivalence of mechanism of action in compounds with high levels of structural similarity. The fifth article in our collection, from Wingen and Stark, deals with a very specific scaffold hop, the variation in amine warheads in advancing novel Histamine H3 antagonists. Molecular recognition in aminergic GPCRs is well understood, but the inherent ‘inflexibility’ of such receptors to accommodate more diverse scaffolds on liganding has long challenged both medicinal chemists and molecular designers. Here, the authors provide an overview of how histamine (or more specifically imidazole) has been successfully taken out of antihistamine (more specifically H3 antagonists) through classical chemical molecular replacement. Juergen Bajorath provides our sixth and final exploration of Scaffold Hopping in molecular design for this collection. In this article the utility and usefulness of molecular fingerprints, long a stalwart of the cheminformatician’s arsenal is explored and detailed. Jeurgen takes on the role of a CSI detective, meticulously dusting for molecular fingerprints to illustrate how, properly deployed, molecular representations as simple as 1D strings can help us move from knowns to novels and the identification of new activity classes. I hope you will enjoy this journey through a diverse and practical set of Scaffold Hopping technologies, With best wishes, David Lloyd
Vol. 10, No. 4 2013
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Approaches to Scaffold Hopping David G. Lloyd University of South Australia, Adelaide SA5000, Australia. Email: ([email protected])
Since the coining of the phrase ‘Scaffold Hopping’ in 1999 – by Gisbert Schneider, one of this issue’s contributors – there have been approximately 200 papers indexed in PubMed which reference or espouse this particular approach to molecular design. These papers encompass and span traditional medicinal chemical, structureinformed, pharmacophore-informed and de novo methodologies with a common objective in all cases to ‘hop’ or move from one molecular structure to a pharmacologically equivalent or superior alternative. There is of course some room for interpretation at an individual level of what exactly a scaffold is, or how far we may move in terms of molecular (dis)similarity to as to be deemed a legitimate ‘hop’ and not simple molecular modification. Alongside the absence of precise definition, the motivation for hopping is myriad – to drive novelty or potency or to move away from potential toxicity or ADME issues or even just simply to challenge the established wisdom prevailing for a given target. Regardless of why it is being done, the end game in any of these approaches should be such that the diversity of liganding exhibited by targets of interest is expanded beyond our initial knowledge or expectation and new scaffolds are advanced with elegant demonstration of rationale and endeavour. Scaffold hops should serve to furnish us with new beacons of activity in previously uncharted chemical space, and map unexplored ligand territory. If done well, these scaffold hops provide diverse and novel compounds which beget additional understanding and research opportunity – or better still meet unmet need with improved profiles in targets relevant to human disease. From my perspective, the very best hops are ones which throw out new branches on the chemical phylogenetic tree for a target, where the move from ‘established’ chemotype to novel agent is one which makes you look twice, and forces the inner chemist to stop and think how could these two compounds (which on the page appear so very different) have equivalent molecular pharmacology. Being forced to stop and think every once in a while is a good thing. 1740-6749/$ ß 2013 Elsevier Ltd. All rights reserved.
This issue of ‘Drug Discovery Today: Technologies’ takes a wide-angle look at Scaffold Hopping through a series of targeted reviews. It is intended to serve both as an introduction to those unfamiliar with the topic, but we also hope it will also give you occasion to pause for thought as we present some of the diverse methodologies. In our six papers we explore different approaches to move from a known active to a structurally distinct novel active. These approaches are presented in the context of their application to various drug design challenges. Our first paper, fittingly, comes from the progenitor of Scaffold Hopping, Gisbert Schneider and covers the use of de novo computational design for Scaffold Hopping. De novo design has significantly advanced from its earliest incarnation wherein scaffolds suggested where often so structurally novel as to be synthetically impossible to produce – which was often spun as ‘idea generators’ to the point where synthetic accessibility, fragment replacement and many other mainstays of the synthetic organic or medicinal chemist are hard coded to the software. Schneider discusses both structure- and ligand-based de novo Scaffold Hopping through examples of their application and highlights areas for future research to further refine the state of the art. David G. Lloyd PhD is the Vice-Chancellor and President of the University of South Australia. He is concurrently Professor of Computer-Aided Drug Design in the University’s Division of Health Sciences. Before his appointment in UniSA in 2013, he was a Professor in the School of Biochemistry and Immunology in Trinity College Dublin, Ireland, where he headed the Molecular Design Group. His research has focused on the development of novel active ligands for targets of biological relevance through the application of computational methodology, driving novelty not only in the ligands themselves but also in the approaches used for the discovery of the ligands. He holds a BSc and PhD from Dublin City University.
http://dx.doi.org/10.1016/j.ddtec.2013.09.001
e451
Drug Discovery Today: Technologies |
The construction of targeted screening libraries continues to furnish novel compounds, hits and leads for pharmaceutical discovery. The molecular diversity of such libraries is a principle concern – ensuring sufficient diversity within a desired pharmacological target window is not straightforward. In their contribution, Sheppard, MacRitchie and Roberts Spearing detail the application of Scaffold Hopping as a key component in their new approach to library design. They detail the combination of iterative structure-based docking and molecular replacement – to furnish a diverse and enhanced set of core scaffold considerations which can be used to furnish screening libraries targeted to specific gene family members. Another major challenge is explored in our third article by Darren Fayne, targeting the inhibition of protein–protein interactions (PPIs) through scaffold hops from big to small molecules. In highlighting the advances in and application of specific computational techniques to tackle PPI inhibitor design, this review explores the issue from to standpoints – can we determine if a given PPI is druggable through computational analysis and if so, what approaches can be taken for depeptidisation and peptidomimetic design – through exploration of specific examples of success in this field. The application of analysis of topology for the exploration of molecular similarity and dissimilarity is explored in the article from Galvez, Galvez-Llompart, Zanni and GarciaDomenech. The authors outline the concept of molecular topology from its origins in mathematical graph theory through to its applications in Scaffold Hopping for the
e452
www.drugdiscoverytoday.com
Vol. 10, No. 4 2013
classification and identification of not only pharmacoequivalent compounds with diverse structures, but also the prediction of non-equivalence of mechanism of action in compounds with high levels of structural similarity. The fifth article in our collection, from Wingen and Stark, deals with a very specific scaffold hop, the variation in amine warheads in advancing novel Histamine H3 antagonists. Molecular recognition in aminergic GPCRs is well understood, but the inherent ‘inflexibility’ of such receptors to accommodate more diverse scaffolds on liganding has long challenged both medicinal chemists and molecular designers. Here, the authors provide an overview of how histamine (or more specifically imidazole) has been successfully taken out of antihistamine (more specifically H3 antagonists) through classical chemical molecular replacement. Juergen Bajorath provides our sixth and final exploration of Scaffold Hopping in molecular design for this collection. In this article the utility and usefulness of molecular fingerprints, long a stalwart of the cheminformatician’s arsenal is explored and detailed. Jeurgen takes on the role of a CSI detective, meticulously dusting for molecular fingerprints to illustrate how, properly deployed, molecular representations as simple as 1D strings can help us move from knowns to novels and the identification of new activity classes. I hope you will enjoy this journey through a diverse and practical set of Scaffold Hopping technologies, With best wishes, David Lloyd
