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The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Finally, through the years, all of the above approaches have given way to modern methods of drug discovery based on the application of structural biology technologies to identify and obtain the structure of biologically relevant target proteins or receptors, followed by the identification of small molecules to accurately interact with them using techniques such as rationale high-throughput screening and/or in silico methods. This top-level approach, which is now considered to be the “cutting edge” of drug discovery, delivered the first Precision Medicines imatinib (GlivecTM) and trastuzumab (HerceptinTM), and is the pathway that most drug discovery companies and academic groups are now following (Figure 2.3). Diagram showing the process of structure-based drug discovery which starts with the structural determination of the drug target (usually a protein or receptor) using X-Ray crystallography or high-field NMR followed by physical or virtual screening to identify a lead molecule.
“Omics” Technologies in Vaccine Research
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
Rashid et al. (2017) followed an interdisciplinary computational framework of genomics, subtractive proteomic, and structural biology approaches using various bioinformatic tools to predict candidate antigens for Pseudomonas aeruginosa. First, the proteome of P. aeruginosa with subcellular localization was screened, and the proteins were analyzed to identify essentiality and virulence. Second, selected proteins were checked for their immuno-protective potential. The crystal structures of these proteins were analyzed to monitor the host-pathogen interactions. Next, broad spectrum immunogenic peptides were identified via epitope prediction, which can bind to various MHC alleles. Lastly, sequences of identified proteins were obtained from different virulent strains to find out the immune-protective consensus sequences among different strains of P. aeruginosa. As a result, two antibiotic efflux pumps, two components of chaperone-usher pathway, a penicillin-binding protein of bacterial cell wall, an extracellular component of type III secretion system, and three uncharacterized secretory proteins were determined as the potential candidate antigens.
Roundabouts
Published in John R. Helliwell, The Whats of a Scientific Life, 2019
Are there other options rather than repeat the whole circle of experiments again? One can try a method altogether different than X-ray crystal structure analysis. A method that has improved a lot in the last ten years or so in my field of structural chemistry and biology is that of cryo electron microscopy. In this case, a crystal is not needed and instead multiple images of a single molecular complex are studied directly. This new method has allowed the breaking out of going round in circles for those impossible-to-crystallise cases. Why were they impossible to crystallise? This could be for a variety of reasons. Firstly, although a homogenously pure sample of these molecules could be prepared, they can each be too flexible to crystallise in a simple, repeating, 3D array. Secondly, it may not have been possible to prepare a pure enough sample for crystallisation. So important is the improved method of cryo electron microscopy for the field of structural biochemistry and structural biology that its lead developers shared the Nobel Prize for Chemistry in 2017: Jacques Dubochet, Joachim Frank and Richard Henderson [2].
Bacterial effluxome as a barrier against antimicrobial agents: structural biology aspects and drug targeting
Published in Tissue Barriers, 2022
Pownraj Brindangnanam, Ajit Ramesh Sawant, K. Prashanth, Mohane Selvaraj Coumar
Many factors are influencing antimicrobial resistance in bacteria; among them, the drug efflux transportation mechanism is an important contributor. Efflux transporters compromise the effectiveness of the antibacterial agents by effluxing them out of the microbe. Ongoing efforts at developing new efflux pump inhibitors (EPIs) for combination chemotherapy is an effective approach to target the efflux transporters, thereby re-sensitizing the drug-resistant microbes to antimicrobial agents. Currently, there are no known EPIs approved for overcoming antimicrobial resistance. In recent years, it is evident that the key to a successful new drug design project is to understand the structural biology aspects of the drug targets (using techniques such as X-ray, NMR and Cryo-EM). Information gathered about the active site (size and shape of the active site, the type of residues present) and the interaction with a ligand/drug molecule (2D/3D interaction of macromolecule-ligand) could help in identifying new lead molecules or help us in the lead optimization/designing of new analogs for the target under investigation.
Novel strategies for the development of hand, foot, and mouth disease vaccines and antiviral therapies
Published in Expert Opinion on Drug Discovery, 2022
Structural biology is the study of molecular structure of biological macromolecules (e.g. RNA, DNA, amino acids, protein, lipids, membranes, viral particles, and antibodies), and understanding how they are constructed, how their structure changes, how their structures affect their functions, and how they affect their interactions are discussed [121]. Macromolecules perform most of the functions in cells, and the formation of specific three-dimensional (3D) structures is required to perform their functions. In the past years, many of studies of X-ray diffraction, Cryo-EM (cryogenic electron microscopy), and computer simulations have established the high-precision physical molecular models for the study of viral structure and function. It has become feasible using highly accurate physical molecular models in in silico study of biological structures. Many 3D models of macromolecules and simulation tools can be found in the Protein Data Bank of NCBI, which all contribute for bioinformatics.
Electron microscopy overview of SARS-COV2 and its clinical impact
Published in Ultrastructural Pathology, 2022
Soheir Saiid Mansy, Mona Mahmoud AbouSamra
Many techniques, including NMR spectroscopy, X-ray solution scattering, neutron diffraction, various spectroscopic techniques, and X-ray crystallography, have been used to determine the shape and structure of biological molecules. Recently, cryo-electron microscopy has become the most effective tool in structural biology after the technical development of its resolutions, which permits the identification of the biomolecular structure in its natural state.59 Cryo-EM has an advantage over X-ray crystallography, and is the most effective tool in analyzing macromolecules during the last few years. Cryo-EM reveals structures in fast-frozen non-crystalline biological samples that are closer to their natural state at an atomic level. In addition, it requires much smaller macromolecule samples to work with, unlike X-ray crystallography, which needs large pieces of materials to optimize the crystallization conditions.59 Hence, cryo-EM has become the tool of choice for determining the structure of macromolecular complexes, especially supra-assemblies that are difficult to prepare in large quantities or virtually inaccessible to crystallize.59,61,62 Identifying the structural biology of viral protein complexes at molecular resolution is important for designing small drug molecules to bind and impair their function.32