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How to Write a Balanced Book Review
Published in John R. Helliwell, Skills for a Scientific Life, 2016
Of my own book reviews, I will allow myself to mention two. My book review of What a Time I Am Having: Selected Letters of Max Perutz [6], A collection brought together by his daughter, Vivien Perutz. In the book review of Early Days of X-ray Crystallography [7], I reviewed the book by an IUCr past president. Andre Authier. The seniority of these two people presented a great challenge to my skills and experience with book reviews. I shared my own insights nevertheless; for example, in my book review of Max Perutz’s letters, I stated the following: Much later in this book I suffered another challenge to my crystallographic beliefs when I came upon the letter written in New York on 1 May 1995 (pp. 467–468) to his son Robin, whom my wife and I know quite well, where Max states ‘I did not find myself shedding many tears for my US colleagues’ shortage of funds. As usual on my visits, most of them have just ‘happened’ to move into new buildings or collected superb new data at Grenoble, or replaced their almost new image plates by a new superior charge something device. Crowds of them are tearing the guts out of structural biology, and most protein structures now emerging resemble one or another seen before’. Whilst structural genomics, to which Max is presumably referring, has excited wide views in the field, pro and con, I was however shocked at his adverse comments on the pace of technological change, which has surely greatly enhanced all aspects of the field of structural molecular biology, and at relatively modest cost.
The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
Aminoacyl-tRNA synthetases are well-validated parasite drug targets (Kalidas et al. 2014, Pham et al. 2014). Having previously solved X-ray crystal structures of T. cruzi histidyl-tRNA synthetase (TcHisRS), T. brucei HisRS, and human cytosolic HisRS (Merritt et al. 2010, Koh et al. 2014), and identified trypanosomal-specific pockets (Koh et al. 2014), Koh et al. (2015) sought to identify chemical starting points for parasite-selective HisRS inhibitors by performing an X-ray crystallographic fragment screen of the Medical Structural Genomics of Pathogenic Protozoa (MSGPP) fragment library. Histidine-complexed TcHisRS crystals were soaked with 68 different fragment cocktails of ten fragments each. Co-crystal structures were solved for fifteen fragments (2.2% hit rate), and all fifteen fragments were observed to bind to the same site—a narrow groove adjacent to the histidine binding site that is not present in the crystal structure without the fragments bound. The site is in very close proximity to the binding site of the adenine ring of the histidyl-AMP reaction intermediate and it is likely that fragment binding will interfere with ATP/histidyl-AMP binding. Although fragment binding was observed by X-ray crystallography, binding of only one of the fifteen fragments could be detected by DSF, when fragments were tested at 1 mM. Additionally, the fragments showed little inhibitory activity in an aminoacylation assay; at a concentration of 2 mM, the most active fragments (including the fragment that gave rise to a thermal shift in the DSF assay) inhibited aminoacylation by 20–39%.
Advances in distributed computing with modern drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Antonio Jesús Banegas-Luna, Baldomero Imbernón, Antonio Llanes Castro, Alfonso Pérez-Garrido, José Pedro Cerón-Carrasco, Sandra Gesing, Ivan Merelli, Daniele D’Agostino, Horacio Pérez-Sánchez
Ligand-based methods (e.g. QSAR, similarity searching, pharmacophore modeling and docking) represent worthwhile solutions in drug discovery. However, QSAR and similarity searching do not take into account knowledge about the binding site within the protein target and this can reduce the accuracy of the calculations. To overcome this issue, structure-based methods are the preferred choice when the 3D structure of the target is known, although they are usually computationally more expensive than ligand-based approaches. In such cases, it is studied how the activity of proteins may be altered when small ligands dock into the well-defined cavities of protein receptors. These ligands can act as molecular switches and control the activity of the protein. For proteins involved in a metabolic pathway related to a disease, artificial ligands can act as drugs [32]. As more metabolic pathways and their associated key proteins are identified, the search for artificial ligands has intensified as a method of improving the treatment of various diseases. The number of known protein structures continues to grow exponentially, a trend increasingly complemented by initiatives in structural genomics [33]. Molecular docking identifies the lead compounds that can bind to a target protein with high affinity [34]. This is achieved by calculating the optimum binding position for each molecule in a large database of potential targets using heuristics and then ranking the database with a scoring function according to the estimated affinity [35].
Small-angle X-ray scattering for the proteomics community: current overview and future potential
Published in Expert Review of Proteomics, 2021
Structural proteomics involves large-scale, high-throughput structural biology of proteins, either in a focused manner or from a broader perspective. A traditional approach to structural proteomics, or structural genomics, in the past two decades has been via high-throughput crystallography, whereby a large number of targets are processed through a structure determination pipeline, and high-resolution 3D structure data are obtained for a limited set of targets – those amenable to crystallization within the pipeline. Hence, at the level of high-throughput proteomics, experimental protein structure information for flexible, disordered, and challenging systems, including membrane proteins, has been lagging behind.
Hot-spot analysis for drug discovery targeting protein-protein interactions
Published in Expert Opinion on Drug Discovery, 2018
Mireia Rosell, Juan Fernández-Recio
The above hot-spot prediction methods are based on the 3D structure of a protein–protein complex. However, despite all the methodological advances and the number of structural genomics projects initiated in recent years, the structural determination of all protein–protein complexes in human (structural interactome) remains one of the biggest challenges in structural biology. Indeed, structural information is available for only a tiny fraction of all the PPIs that are estimated to occur in human [14]. In this context, a variety of computational approaches have been reported to help characterizing a PPI for which there is no structural information.