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The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Analogous to Lipinski’s “Rule of Five”, it has been proposed that ideal fragments for FBDD should follow a “rule of three” (i.e., molecular weight < 300, ClogP < 3, the number of hydrogen bond donors and acceptors < 3). Although such fragments have relatively low affinity for their targets, they have high water solubility so they can be screened at higher concentrations. However, the low binding affinities pose significant challenges for screening, and so many biophysical techniques have been investigated to address this issue such as NMR, Surface Plasmon Resonance (SPR), Isothermal Titration Calorimetry (ITC), and Microscale Thermophoresis (MST). Once a fragment (or a combination of fragments) has been identified, protein X-ray crystallography can then be used to obtain structural models of the protein-fragment complex. This information is then used to guide the synthesis of higher-affinity ligands.
Therapeutic Strategies and Future Research
Published in Mark A. Mentzer, Mild Traumatic Brain Injury, 2020
X-ray crystallography provides another means to characterize the atomic structure of crystalline materials. (Rosalind Franklin used the technique to produce the famous demonstration that DNA is helical.) This characterization includes proteins and nucleic acids. While certain proteins are difficult to crystallize, nearly 50,000 proteins, nucleic acids and other biological macromolecules have now been measured with X-ray crystallography (Scapin, 2006; Lundstrom, 2006).
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
The determination of the exact structure of the ligand-binding pocket within the DARs has long been a challenging endeavor. Scientists typically resolve the chemical structure of a protein by means of X-ray crystallography. For that, various methods are used to induce the protein to condense into a tightly packed crystal lattice. Once this is achieved, X-rays are delivered to the crystal and the structure of the protein is resolved from the diffraction patterns. However, getting the DAR proteins to crystalize with a bound ligand had been problematic for many years. This difficulty stems from the fact that membrane-embedded receptors are notoriously difficult proteins for crystallization because of their low abundance and hydrophobicity. In fact, of the five DAR subtypes, only the D3R has been successfully crystallized.
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
Targeting thermoTRP ion channels: in silico preclinical approaches and opportunities
Published in Expert Opinion on Therapeutic Targets, 2020
Gregorio Fernández-Ballester, Asia Fernández-Carvajal, Antonio Ferrer-Montiel
X-ray crystallography has been the traditional tool used by structural biologists to solve protein structures. To date, about 160,000 protein structures have been published in the Protein Data Bank (PDB), with near 10,000 new structures added every year. For X-ray crystallography, the target protein has to be expressed, purified near to homogeneity to obtain protein crystals with good diffraction patterns. Diffracting crystals are essential for building an accurate structural model where the three-dimensional spatial position of each atom can be mapped. An important limiting step in protein crystallization is to empirically establish the conditions for getting diffracting protein crystals. Presently, concentrated protein solutions are subjected in parallel to a wide variety of crystallization conditions using the drop diffusion technique. This technique allows the screening of a variety of crystallization conditions close to an HTS format.
Fragment-based screening with natural products for novel anti-parasitic disease drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Crystallographic fragment screening is one of the major techniques for FBDD in which protein crystals are soaked with high concentrations of fragments. Specific binding of ligands to the protein is detected from analysis of X-ray diffraction data collected from crystals. The main advantage of X-ray crystallography is it can provide an immediate model of the fragment binding to the protein, however, the main disadvantage is that it requires a suitable crystal system for compounds bound to target proteins that can be a major issue for some targets [40]. Crystallographic fragment screening was used to find inhibitors of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase (TbNDRT) [41]. Thirty-one fragment cocktails were generated from 304 commercially available fragments by mixing 7–10 compounds into one cocktail based on chemical properties. Co-crystallographic screening of the 31 cocktails with TbNDRT resulted in 69 crystals, in which four ligands (49–52) (Figure 12) were identified in the active site. The four ligands were screened against bloodstream form T. brucei cell cultures, all showing growth inhibition effects with ED50 between 0.12 and 1.34 mM.