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Jurgen Bajorath - One of the best experts on this subject based on the ideXlab platform.
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Advances in Activity Cliff Research.
Molecular Informatics, 2016Co-Authors: Dilyana Dimova, Jurgen BajorathAbstract:Activity Cliffs, i.e. similar compounds with large potency differences, are of interest from a chemical and informatics viewpoint; as a source of structure-activity relationship information, for compound optimization, and activity prediction. Herein, recent highlights of activity cliff research are discussed including studies that have further extended our understanding of activity Cliffs, yielded unprecedented insights, or paved the way for practical applications.
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identification and analysis of the currently available high confidence three dimensional activity Cliffs
RSC Advances, 2015Co-Authors: Norbert Furtmann, Michael Gutschow, Jurgen BajorathAbstract:Three-dimensional activity Cliffs (3D-Cliffs) were determined on the basis of the X-ray structures of protein–ligand complexes currently available in the Protein Data Bank (PDB). For a given target, all the bound small molecular ligands were compared in a pairwise manner and ligand pairs with at least 80% 3D similarity of their binding modes and an at least 100-fold difference in potency were identified and classified as 3D-Cliffs. Only high-confidence activity data were considered. All the 3D-Cliffs were subjected to visual inspection and categorized according to ligand–target interaction differences. In addition, relationships between 3D-Cliffs were systematically explored. Compared to a previous survey, in which 216 3D-Cliffs were detected, the current study identified a total of 630 3D-Cliffs that involved 580 unique ligands with activity against 61 human targets belonging to 25 families. Thus, over the past few years, there has been significant growth in high-confidence activity cliff information at the structural level. Notable increases in the number of 3D-Cliffs were observed for a number of different targets, in particular, proteases. The pool of currently available 3D-Cliffs provides a rich source of information for structure–activity relationship (SAR) analysis and structure-based design.
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Activity Cliff Networks for Medicinal Chemistry
Drug Development Research, 2014Co-Authors: Dagmar Stumpfe, Jurgen BajorathAbstract:Preclinical Research Network representations are widely used in bioinformatics but have only been little explored in chemistry. Thus far, only a few attempts have been made to generate and analyze compound networks. Among these are the first activity cliff networks. In medicinal chemistry, activity Cliffs are focal points of structure–activity relationships (SAR) analysis. Activity Cliffs have generally been defined as pairs of structurally similar or analogous active compounds that have a large difference in potency against their target. However, most activity Cliffs are not formed in isolation but in a coordinated manner involving multiple highly and weakly potent compounds. Recently, a comprehensive activity cliff network has been generated for current public domain bioactive compounds, hence providing a first global view of activity cliff formation. The design of activity cliff networks is discussed herein. From the global activity cliff network, local networks can be extracted for individual compound activity classes that provide graphical access to high-level SAR information for compound optimization efforts.
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Comprehensive Analysis of Three-Dimensional Activity Cliffs Formed by Kinase Inhibitors with Different Binding Modes and Cliff Mapping of Structural Analogues
Journal of Medicinal Chemistry, 2014Co-Authors: Norbert Furtmann, Jurgen BajorathAbstract:Kinases are among the structurally most extensively characterized therapeutic targets. For many kinases, X-ray structures of inhibitor complexes are publicly available. We have identified all three-dimensional activity Cliffs (3D-Cliffs) formed by kinase inhibitors. More than 1300 X-ray structures of unique kinase-inhibitor complexes and associated activity data were analyzed. On the basis of binding mode comparison and 3D similarity calculations, 105 3D-Cliffs were detected for type I, type II, or type III inhibitors of 13 different kinases. Many of these activity Cliffs revealed clear interaction differences between highly and weakly potent inhibitors. More than 200 structural analogues of 3D-cliff compounds were identified whose structure–activity relationships (SARs) can be further explored in three dimensions on the basis of the corresponding 3D-Cliffs. In addition to SAR exploration, 3D-Cliffs provide useful interaction hypotheses for structure-based design. The kinase inhibitor and activity cliff i...
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method for the evaluation of structure activity relationship information associated with coordinated activity Cliffs
Journal of Medicinal Chemistry, 2014Co-Authors: Dilyana Dimova, Dagmar Stumpfe, Jurgen BajorathAbstract:Activity Cliffs are generally defined as pairs of active compounds having a large difference in potency. Although this definition of activity Cliffs focuses on compound pairs, the vast majority of Cliffs are formed in a coordinated manner. This means that multiple highly and weakly potent compounds form series of activity Cliffs, which often overlap. In activity cliff networks, coordinated Cliffs emerge as disjoint activity cliff clusters. Recently, we have identified all cliff clusters from current bioactive compounds and analyzed their topologies. For structure–activity relationship (SAR) analysis, activity cliff clusters are of high interest, since they contain more SAR information than Cliffs that are individually considered. For medicinal chemistry applications, a key question becomes how to best extract SAR information from activity cliff clusters. This represents a challenging problem, given the complexity of many activity cliff configurations. Herein we introduce a generally applicable methodology...
David N Petley - One of the best experts on this subject based on the ideXlab platform.
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erosional processes in the hard rock coastal Cliffs at staithes north yorkshire
Geomorphology, 2010Co-Authors: Michael Lim, Nick Rosser, Robert J Allison, David N PetleyAbstract:The processes of change on near-vertical coastal Cliffs have been quantified using terrestrial photogrammetry and laser scanning. The approach allows discrete rockfall geometry to be measured, and source located in three dimensions. This paper presents the analysis of an inventory of over 100000 discrete rockfalls, recorded from the Liassic coast at Staithes, North Yorkshire (UK), where a rock face area of over 16000 m(2) has been monitored over a 20 month period. The data obtained on three-dimensional scar geometry and source position give an insight into rockfall characteristics from a range of rock types, cliff heights and geometries. Multiple failure mechanisms such as overhang collapse, constant spalling, fragmentation and large scale, coherent rockfalls have been observed and related to rock-type controlled processes on the rock face. The spatially referenced rockfall scar data are used to assess the influence of environmental controls on variable rock mass properties, such as rock type, structure and cliff geometry. Analysis of rockfall magnitude-frequency reveals notable similarities between coastal rockfalls and inventories from non-coastal environments. The resolution of the monitoring data allows quantification of rockfalls down to volumes of 1.25 x 10(-4) m(3) to be consistently sampled and measured. This complete magnitude-frequency relationship suggests that rather than evolving exclusively through isolated, sporadic losses, coastal cliff geomorphology reflects interconnected processes in which each rockfall is part of a continuum of change to the rock face. Further detailed assessment of the rock face reveals the control of the pre-failure morphology on subsequent failure patterns, for example, the quantity of rock protrusion from the cliff is positively correlated with subsequent failure volume. The continuum of activity and the controls on failure identified within these data suggest that the episodic behaviour of coastal Cliffs previously assumed may have been overstated by coarser resolution monitoring data. The findings improve our understanding of the evolution of coastal Cliffs and highlight areas for further research into both cliff processes and the character of rock slope failures in general.
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terrestrial laser scanning for monitoring the process of hard rock coastal cliff erosion
Quarterly Journal of Engineering Geology and Hydrogeology, 2005Co-Authors: Nick Rosser, Michael Lim, David N Petley, Stuart Dunning, Robert J AllisonAbstract:Hard rock Cliffs represent approximately 75% of the world9s coastline. The rate and nature of the mechanisms that govern the retreat of these Cliffs remain poorly constrained, primarily because conventional approaches employed to monitor these processes are generally inadequate for describing cliff erosion processes directly. These techniques are usually centred upon the interpretation of data collected periodically from aerial sensors, including stereographic aerial photographs and more recently air-borne LIDAR. These methods are generally not capable of assessing the pattern of erosion on the cliff face due to the oblique viewing angles, and hence tend to concentrate upon the resultant recession of the cliff top rather than change on the cliff face. Thus, processes of undercutting and small scale iterative failures of localized sections of the cliff face are generally not recorded. It is only when a failure affects the cliff top that any retreat is recorded. It is therefore unsurprising that cliff erosion is commonly deemed to be episodic. This paper presents a new approach to detailed cliff process monitoring using terrestrial laser scanning (TLS), which directly monitors changes on coastal cliff faces. The method allows the quantification of failures ranging in scale from the detachment of blocks of a few centimetres in dimension through to large rock, debris or soil, falls, slides and flows over 1000 m 3 . The collection of data is on-site and rapid and hence cost effective, providing a detailed description of the nature of coastal cliff erosion. This paper describes the methodological approach and demonstrates the range of results which can be generated, here shown for 16 months of monitoring data collected for a near-vertical cliff section on the coast of North Yorkshire, UK. The results demonstrate that terrestrial laser scanning can be used to quantify cliff failures to a previously unobtainable precision. The results reveal a strong spatial and temporal pattern of cliff collapse which contradicts commonly held perceptions of the nature of coastal cliff development.
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combined digital photogrammetry and time of flight laser scanning for monitoring cliff evolution
Photogrammetric Record, 2005Co-Authors: David N Petley, Nick Rosser, Robert J Allison, Antony J Long, David PybusAbstract:Although Cliffs form approximately 75% of the world's coastline, the understanding of the processes through which they evolve remains limited because of a lack of quantitative data on the morphological changes they undergo. In this paper the combination of terrestrial time-of-flight laser scanning with high-resolution digital photogrammetry is examined to generate high-quality data-sets pertaining to the geomorphic processes governing cliff development. The study was undertaken on a section of hard rock Cliffs in North Yorkshire, UK, which has been monitored over a 12-month period. High-density, laser-scanned point clouds have been used to produce an accurate representation of these complex surfaces, free from the optical variations that degrade photographic data. These data-sets have been combined with high-resolution photographic monitoring, resampled with the fixed accuracies of the terrestrial laser survey, to generate a new approach to recording the volumetric changes in complex coastal Cliffs. This has led to significant improvements in the understanding of the activity patterns of coastal Cliffs.
F. Berger - One of the best experts on this subject based on the ideXlab platform.
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Quantification of cliff retreat in coastal Quaternary sediments using anatomical changes in exposed tree roots
Earth Surface Processes and Landforms, 2018Co-Authors: J. Lopez-saez, C. Corona, Patrice Morel, G. Rovera, T.j.b. Dewez, M. Stoffel, F. BergerAbstract:Sea Cliffs represent 80% of the world's coasts and can be found virtually in all types of morphogenetic environments. Most studies on rocky environments focused on the impacts of modern sea level rise on cliff stability derived from sequential surveys, direct measurements or erosional features in anthropogenic structures. In this study, we explore the potential of dendrogeomorphic techniques to quantify multidecadal changes in coastal environments on Porquerolles Island (France). We sampled a total of 56 cross-sections from 16 Pinus halepensis Mill. roots growing on former alluvial deposits and on sandy-gravelly Cliffs to quantify mean annual cliff retreat rates as well as changes in cliff geometry. Anatomical changes in roots have been used successfully in the past to quantify continuous denudation rates on slopes, channel incision and gullying processes but the approach has not been used so far in a coastal cliff context. At Porquerolles Island, reconstructed rates of cliff retreat cover 30-40 years and show average erosion rates between 0.6 and 3.9 cm yr(-1) (average: 2.1 cm yr(-1)). Highest rates are observed at Pointe de la Tufiere (2.6-3.9 cm yr(-1)), a small rock promontory that is more exposed to wave and storm surges than the remainder of the study area. By contrast, lower erosion rates are recorded at Cliffs protected by the La Courtade pocket beach (0.6-1.9 cm yr(-1)). This contribution demonstrates that dendrogeomorphic analyses of roots clearly have a significant potential and that they are a powerful tool for the quantification of multidecadal rates of cliff retreat in areas where measurements of past erosion are lacking. More specifically, the approach also has clear advantages over the shorter time series obtained with repeat monitoring (e.g. terrestrial laser scanning, sensors, erosion pins) or over longer, but more coarsely resolved records obtained from aerial photographs or radio-nuclides.
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Preliminary quantification of the erosion of sandy-gravelly Cliffs on the island of Porquerolles (Provence, France) through dendrogeomorphology, using exposed roots of Aleppo pine (Pinus halepensis Mill.)
Geografia Fisica e Dinamica Quaternaria, 2013Co-Authors: G. Rovera, J. Lopez-saez, C. Corona, M. Stoffel, F. BergerAbstract:This study is a first attempt to specify the geodynamic processes leading to the erosion of detrital quaternary Cliffs on the island of Porquerolles, and to quantify the rate of erosion by means of dendrogeomorphology. The island is located in the Mediterranean Sea, off the coast of Provence (France). This method identifies the roots of Aleppo pine (Pinus halepensis Mill.) that have been unearthed by cliff retreat. The year of denudation is revealed by the net change in tracheid anatomy in tree rings, so that the retreating rates of Cliffs can be established and the ratio between the distance of loosening and the number of years since denudation can be assessed. 13 root samples were used to determine that the cliff retreat is due to small rockfalls, at an average rate of 2.5 cm/a. This value is compared to other rates of erosion quantified on rocky or sandy shores. A review of the method and a comparison with methods based on photogrammetry and micrometrics are proposed.
Tsuguo Sunamura - One of the best experts on this subject based on the ideXlab platform.
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rocky coast processes with special reference to the recession of soft rock Cliffs
Proceedings of the Japan Academy. Series B Physical and biological sciences, 2015Co-Authors: Tsuguo SunamuraAbstract:Substantial progress in research on the recession of coastal Cliffs composed of soft materials has been made in recent years and data with higher accuracy have been accumulated. This paper provides the state of the art review in the recession studies and highlights two new findings obtained from the reanalysis of existing data. The review topics are: episodic and localized nature of cliff recession; the development of cliffline; the relationship between cliff height and recession rate; mechanisms of cliff toe erosion by waves; a fundamental equation for wave-induced toe erosion; factors controlling toe erosion; and slope instabilities and mass movements. The findings are presented on (1) the temporal change in cliffline recession mode and (2) the effect of beach sediment at the cliff base on the cliff erosion.
Nick Rosser - One of the best experts on this subject based on the ideXlab platform.
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erosional processes in the hard rock coastal Cliffs at staithes north yorkshire
Geomorphology, 2010Co-Authors: Michael Lim, Nick Rosser, Robert J Allison, David N PetleyAbstract:The processes of change on near-vertical coastal Cliffs have been quantified using terrestrial photogrammetry and laser scanning. The approach allows discrete rockfall geometry to be measured, and source located in three dimensions. This paper presents the analysis of an inventory of over 100000 discrete rockfalls, recorded from the Liassic coast at Staithes, North Yorkshire (UK), where a rock face area of over 16000 m(2) has been monitored over a 20 month period. The data obtained on three-dimensional scar geometry and source position give an insight into rockfall characteristics from a range of rock types, cliff heights and geometries. Multiple failure mechanisms such as overhang collapse, constant spalling, fragmentation and large scale, coherent rockfalls have been observed and related to rock-type controlled processes on the rock face. The spatially referenced rockfall scar data are used to assess the influence of environmental controls on variable rock mass properties, such as rock type, structure and cliff geometry. Analysis of rockfall magnitude-frequency reveals notable similarities between coastal rockfalls and inventories from non-coastal environments. The resolution of the monitoring data allows quantification of rockfalls down to volumes of 1.25 x 10(-4) m(3) to be consistently sampled and measured. This complete magnitude-frequency relationship suggests that rather than evolving exclusively through isolated, sporadic losses, coastal cliff geomorphology reflects interconnected processes in which each rockfall is part of a continuum of change to the rock face. Further detailed assessment of the rock face reveals the control of the pre-failure morphology on subsequent failure patterns, for example, the quantity of rock protrusion from the cliff is positively correlated with subsequent failure volume. The continuum of activity and the controls on failure identified within these data suggest that the episodic behaviour of coastal Cliffs previously assumed may have been overstated by coarser resolution monitoring data. The findings improve our understanding of the evolution of coastal Cliffs and highlight areas for further research into both cliff processes and the character of rock slope failures in general.
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Exploring energy delivery to coastal rock Cliffs
2009Co-Authors: Emma Norman, Nick Rosser, Michael Lim, David PetleyAbstract:This study uses microseismic ground motion as a proxy for energy delivery to a rock coastal cliff to examine the contributions of three key forcing mechanisms: waves, tides and storms. The energy delivered to hard rock Cliffs from waves, tides and storms is acknowledged as a key control of cliff erosion, due to the influence on the effectiveness of mechanical and hydraulic processes. The direct impact and variability of wave energy and its influence on rock Cliffs however is poorly constrained. Questions remain around the relative impact that waves, tides and storms have on energy delivery to the coast and the relative significance of marine to sub-aerial weathering processes in controlling cliff failure is unknown.
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terrestrial laser scanning for monitoring the process of hard rock coastal cliff erosion
Quarterly Journal of Engineering Geology and Hydrogeology, 2005Co-Authors: Nick Rosser, Michael Lim, David N Petley, Stuart Dunning, Robert J AllisonAbstract:Hard rock Cliffs represent approximately 75% of the world9s coastline. The rate and nature of the mechanisms that govern the retreat of these Cliffs remain poorly constrained, primarily because conventional approaches employed to monitor these processes are generally inadequate for describing cliff erosion processes directly. These techniques are usually centred upon the interpretation of data collected periodically from aerial sensors, including stereographic aerial photographs and more recently air-borne LIDAR. These methods are generally not capable of assessing the pattern of erosion on the cliff face due to the oblique viewing angles, and hence tend to concentrate upon the resultant recession of the cliff top rather than change on the cliff face. Thus, processes of undercutting and small scale iterative failures of localized sections of the cliff face are generally not recorded. It is only when a failure affects the cliff top that any retreat is recorded. It is therefore unsurprising that cliff erosion is commonly deemed to be episodic. This paper presents a new approach to detailed cliff process monitoring using terrestrial laser scanning (TLS), which directly monitors changes on coastal cliff faces. The method allows the quantification of failures ranging in scale from the detachment of blocks of a few centimetres in dimension through to large rock, debris or soil, falls, slides and flows over 1000 m 3 . The collection of data is on-site and rapid and hence cost effective, providing a detailed description of the nature of coastal cliff erosion. This paper describes the methodological approach and demonstrates the range of results which can be generated, here shown for 16 months of monitoring data collected for a near-vertical cliff section on the coast of North Yorkshire, UK. The results demonstrate that terrestrial laser scanning can be used to quantify cliff failures to a previously unobtainable precision. The results reveal a strong spatial and temporal pattern of cliff collapse which contradicts commonly held perceptions of the nature of coastal cliff development.
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combined digital photogrammetry and time of flight laser scanning for monitoring cliff evolution
Photogrammetric Record, 2005Co-Authors: David N Petley, Nick Rosser, Robert J Allison, Antony J Long, David PybusAbstract:Although Cliffs form approximately 75% of the world's coastline, the understanding of the processes through which they evolve remains limited because of a lack of quantitative data on the morphological changes they undergo. In this paper the combination of terrestrial time-of-flight laser scanning with high-resolution digital photogrammetry is examined to generate high-quality data-sets pertaining to the geomorphic processes governing cliff development. The study was undertaken on a section of hard rock Cliffs in North Yorkshire, UK, which has been monitored over a 12-month period. High-density, laser-scanned point clouds have been used to produce an accurate representation of these complex surfaces, free from the optical variations that degrade photographic data. These data-sets have been combined with high-resolution photographic monitoring, resampled with the fixed accuracies of the terrestrial laser survey, to generate a new approach to recording the volumetric changes in complex coastal Cliffs. This has led to significant improvements in the understanding of the activity patterns of coastal Cliffs.
