Molecular Modelling of PDE3A Catalytic Domain

Recent studies have highlighted the clinical benefits of regulating phosphodiesterase-3 enzymes. Inhibition of PDE3A has proven to aid in preventing and treating cardiovascularrelated disorders and platelet dysfunction. Hypothermia is a condition that can cause cardiac arrest. However, there are no suitable inotropic drugs that are effective for use under hypothermic conditions. Being able to understand the properties and function of the PDE3A enzyme is therefore essential to the development of new drug inhibitors with exceeding potency. The challenge remains unresolved due to the scarcity of PDE3A crystal structure information. In this study, three models of the PDE3A enzyme were created based on homology modelling. The aim of creating homology models of the PDE3A enzyme was to visualize and gather further structural information for future studies related to drug development. The models were constructed by using known 3D structures of evolutionarily related proteins. The PDB IDs of the three chosen templates were 1SO2, 1TAZ and 4NPV. The quality of the models was evaluated using PROCHECK and ERRAT. The three constructed models were all of high quality and fitted well to their corresponding templates. However, the 1SO2-based model proved to be the most reliable and therefore suitable for virtual ligand screening procedure to identify potential binding compounds that can be used as PDE3A inhibitors. The overview of the active site interactions of the models revealed that residues Y751, T844, D950, F972, Q975 and F1004 are highly conserved and presumably essential for enzymatic activity and ligand binding. The structural information of the PDE3A models is a significant asset for the development of PDE3A drug inhibitors that are suitable for use under hypothermic conditions

their morphological and seismic characterisation from selected Atlantic high productivity regions

Sediment transport, high productivity, submarine canyon, submarine slide, excess pore-pressure, weak layers, slope failure. - The study investigates processes of mass sediment transport in two geologically unique Atlantic margins influenced by high primary productivity, i.e. the Mauritanian and Uruguayan margins. Whereas the Mauritanian margin is dominated by hyper-arid conditions, the Uruguayan margin, on the other hand, is dominated by fluvial sediment inputs. Investigations of the Mauritanian margin are centred on two major features, i.e. the Cap Timiris Canyon and the Mauritania Slide Complex, using combined analyses of hydroacoustic and high resolution multi-channel seismic (MCS) data. An area offshore Uruguay, which is dominated by extensive slope instabilities and mass sediment transport, was also investigated with high resolution MCS data. Results of the study suggest ...thesi

Implications of structural inheritance in oblique rift zones for basin compartmentalization: Nkhata Basin, Malawi Rift (EARS)

The Cenozoic East African Rift System (EARS) is an exceptional example of active continental extension, providing opportunities for furthering our understanding of hydrocarbon plays within rifts. It is divided into structurally distinct western and eastern branches. The western branch comprises deep rift basins separated by transfer zones, commonly localised onto pre-existing structures, offering good regional scale hydrocarbon traps. At a basin-scale, local discrete inherited structures might also play an important role on fault localisation and hydrocarbon distribution. Here, we consider the evolution of the Central basin of the Malawi Rift, in particular the influence of pre-existing structural fabrics.Integrating basin-scale multichannel 2D, and high resolution seismic datasets we constrain the border, Mlowe-Nkhata, fault system (MNF) to the west of the basin and smaller Mbamba fault (MF) to the east and document their evolution. Intra basin structures define a series of horsts, which initiated as convergent transfers, along the basin axis. The horsts are offset along a NE-SW striking transfer fault parallel to and along strike of the onshore Karoo (Permo-Triassic) Ruhuhu graben. Discrete pre-existing structures probably determined its location and, oriented obliquely to the extension orientation it accommodated predominantly strike-slip deformation, with more slowly accrued dip-slip.To the north of this transfer fault, the overall basin architecture is asymmetric, thickening to the west throughout; while to the south, an initially symmetric graben architecture became increasingly asymmetric in sediment distribution as strain localised onto the western MNF. The presence of the axial horst increasingly focussed sediment supply to the west. As the transfer fault increased its displacement, so this axial supply was interrupted, effectively starving the south-east while ponding sediments between the western horst margin and the transfer fault. This asymmetric bathymetry and partitioned sedimentation continues to the present-day, overprinting the early basin symmetry and configuration. Sediments deposited earlier become increasingly dissected and fault juxtapositions changed at a small (10-100 m) scale. The observed influence of basin-scale transfer faults on sediment dispersal and fault compartmentalization due to pre-existing structures oblique to the extension orientation is relevant to analogous exploration settings

Molecular modeling of 3D structure of the oxytocin receptor. Discovery of novel oxytocin receptor agonists via molecular docking studies.

Oxytocin has been shown to be implicated in psychiatric diseases such as depression, anxiety disorders, autism post-traumatic stress disorder, and schizophrenia. As a result, oxytocin can be used as a potential treatment for these brain disorders. However, oxytocin is a large peptide, and is therefore unable to cross the blood brain barrier. Thus, the development of new small non-peptide drugs would be of great benefit in the treatment of these neurological disorders. In this study, new non-peptide agonists have been proposed based on homology modeling and virtual ligand screening. There is no available experimentally solved structure of the oxytocin receptor; hence three models are constructed and refined using known 3D crystal structures of evolutionary related proteins (PDB: 2Y00, PDB: 4BVN and PDB: 4LDE). The ability of the three models to discriminate between true ligands and decoys was tested and analyzed using the Receiver operating characteristics (ROC) curve. A virtual ligand screening procedure was applied on the most suitable of the 3 models (4LDE-based model) in order to identify potential binding compounds that can be used as oxytocin receptor agonists. The results obtained from this study are 15 compounds, which can be tested in vivo and eventually used as potential drug candidates

Molecular modeling of 3D structure of the oxytocin receptor. Discovery of novel oxytocin receptor agonists via molecular docking studies.

Oxytocin has been shown to be implicated in psychiatric diseases such as depression, anxiety disorders, autism post-traumatic stress disorder, and schizophrenia. As a result, oxytocin can be used as a potential treatment for these brain disorders. However, oxytocin is a large peptide, and is therefore unable to cross the blood brain barrier. Thus, the development of new small non-peptide drugs would be of great benefit in the treatment of these neurological disorders. In this study, new non-peptide agonists have been proposed based on homology modeling and virtual ligand screening. There is no available experimentally solved structure of the oxytocin receptor; hence three models are constructed and refined using known 3D crystal structures of evolutionary related proteins (PDB: 2Y00, PDB: 4BVN and PDB: 4LDE). The ability of the three models to discriminate between true ligands and decoys was tested and analyzed using the Receiver operating characteristics (ROC) curve. A virtual ligand screening procedure was applied on the most suitable of the 3 models (4LDE-based model) in order to identify potential binding compounds that can be used as oxytocin receptor agonists. The results obtained from this study are 15 compounds, which can be tested in vivo and eventually used as potential drug candidates

Sedimenttransportprozesse in Kanälen und am offenen Hang: morphologische und seismische Charakterisierung in ausgewählten Hochproduktionsgebieten im Atlantik

The study investigates processes of mass sediment transport in two geologically unique Atlantic margins influenced by high primary productivity, i.e. the Mauritanian and Uruguayan margins. Whereas the Mauritanian margin is dominated by hyper-arid conditions, the Uruguayan margin, on the other hand, is dominated by fluvial sediment inputs. Investigations of the Mauritanian margin are centred on two major features, i.e. the Cap Timiris Canyon and the Mauritania Slide Complex, using combined analyses of hydroacoustic and high resolution multi-channel seismic (MCS) data. An area offshore Uruguay, which is dominated by extensive slope instabilities and mass sediment transport, was also investigated with high resolution MCS data. Results of the study suggest margin physiography have played a key role in pre-determining the style of mass sediment transport which, in both margins, is characterised by a sharp transition from channelised flow processes to large scale mass sediment movements in open slope environments. Entry points of major fluvial systems along the coast were likely to have given rise to canyon processes which were significantly enhanced by the presence of regional structural lineations as in the case of Cap Timiris Canyon. The open slope areas allowed undisturbed rapid sediment build-up leading to extensive slope instabilities. Build-up of excess pore-pressures constitutes the most important trigger mechanism for the large-scale sediment failures in both margins. The mass sediment movements were facilitated by widespread lithological weak layers which were exploited as glide planes. The high marine productivity in the regions significantly elevated organic inputs into both margins and, consequently, enhanced the generation of excess pore pressures as well as the formation of the mud-rich lithologic weak layers. The thesis provides fundamental insights for understanding canyon processes and open slope mass sediment movement along passive continental margins influenced by high productivity

Molecular Modelling of PDE3A Catalytic Domain

Recent studies have highlighted the clinical benefits of regulating phosphodiesterase-3 enzymes. Inhibition of PDE3A has proven to aid in preventing and treating cardiovascularrelated disorders and platelet dysfunction. Hypothermia is a condition that can cause cardiac arrest. However, there are no suitable inotropic drugs that are effective for use under hypothermic conditions. Being able to understand the properties and function of the PDE3A enzyme is therefore essential to the development of new drug inhibitors with exceeding potency. The challenge remains unresolved due to the scarcity of PDE3A crystal structure information. In this study, three models of the PDE3A enzyme were created based on homology modelling. The aim of creating homology models of the PDE3A enzyme was to visualize and gather further structural information for future studies related to drug development. The models were constructed by using known 3D structures of evolutionarily related proteins. The PDB IDs of the three chosen templates were 1SO2, 1TAZ and 4NPV. The quality of the models was evaluated using PROCHECK and ERRAT. The three constructed models were all of high quality and fitted well to their corresponding templates. However, the 1SO2-based model proved to be the most reliable and therefore suitable for virtual ligand screening procedure to identify potential binding compounds that can be used as PDE3A inhibitors. The overview of the active site interactions of the models revealed that residues Y751, T844, D950, F972, Q975 and F1004 are highly conserved and presumably essential for enzymatic activity and ligand binding. The structural information of the PDE3A models is a significant asset for the development of PDE3A drug inhibitors that are suitable for use under hypothermic conditions

Channelised and Open-slope processes of mass sediment transport: their morphological and seismic characterisation from selected Atlantic high productivity regions

The study investigates processes of mass sediment transport in two geologically unique Atlantic margins influenced by high primary productivity, i.e. the Mauritanian and Uruguayan margins. Whereas the Mauritanian margin is dominated by hyper-arid conditions, the Uruguayan margin, on the other hand, is dominated by fluvial sediment inputs. Investigations of the Mauritanian margin are centred on two major features, i.e. the Cap Timiris Canyon and the Mauritania Slide Complex, using combined analyses of hydroacoustic and high resolution multi-channel seismic (MCS) data. An area offshore Uruguay, which is dominated by extensive slope instabilities and mass sediment transport, was also investigated with high resolution MCS data. Results of the study suggest margin physiography have played a key role in pre-determining the style of mass sediment transport which, in both margins, is characterised by a sharp transition from channelised flow processes to large scale mass sediment movements in open slope environments. Entry points of major fluvial systems along the coast were likely to have given rise to canyon processes which were significantly enhanced by the presence of regional structural lineations as in the case of Cap Timiris Canyon. The open slope areas allowed undisturbed rapid sediment build-up leading to extensive slope instabilities. Build-up of excess pore-pressures constitutes the most important trigger mechanism for the large-scale sediment failures in both margins. The mass sediment movements were facilitated by widespread lithological weak layers which were exploited as glide planes. The high marine productivity in the regions significantly elevated organic inputs into both margins and, consequently, enhanced the generation of excess pore pressures as well as the formation of the mud-rich lithologic weak layers. The thesis provides fundamental insights for understanding canyon processes and open slope mass sediment movement along passive continental margins influenced by high productivity