China
Africa
Explore chapters and articles related to this topic
The Inducible System: Antigens
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The sites on an antigen that are recognized by antibodies (epitopes) may be conformational or sequential (Figure 6.3). A conformational site is any surface shape determined by the complex folding of the molecule. The conformational site is analogous to a mountain range on the surface of the earth which results from continental drift and the crushing together of rock strata. The conformational sites of proteins may be determined by widely separated stretches of amino acid sequences that are brought into proximity by the folding of the polypeptide. Thus, conformational sites are lost with denaturation of molecules, a process which destroys secondary and tertiary structure.
Nanomedicine(s) under the Microscope *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Many of the simplified cartoons drawn in publications (including those shown in Fig. 13.2) to illustrate the authors’ vision of their idealized nanostructure are frequently too naive and/or too perfect to give an accurate impression. Often the components are not presented to scale one to another, and the conformation suggested may also be very misleading. Classical examples include the following: PEGylated liposomes where the polymer is only shown externally disposed (it can also be internally disposed); polymer-drug conjugates do not exist in solution as the Ringsdorf “washing line model” implies [21]; in aqueous solutions conjugates form unimolecular micelles with hydrophobic drugs in the interior [176]; dendrimer conformation depends on generation and pendant group chemistry (they are not all perfectly substituted small spherical particles); and polymers conjugated to surfaces (e.g., carbon nanotubes and nanoparticles) may lie on the surface rather than extend outward into solution—it depends on surface and polymer chemistry. Many structures can also dynamically change their conformation in solution depending on local salt concentration, polyelectrolyte counterion, and local pH and/or during degradation of the components. Some of the biological barriers relevant to studies on structure-activity relationships are summarized in Fig. 13.8a.
A Brief Background
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The way in which these molecules are drawn does not portray their three-dimensional structure, which is important because molecules with the same structural formula can be arranged differently in space to produce stereoisomerism. Molecules are continuously moving and vibrating and rotation around single bonds, which means that they can adopt different conformations. Molecules with the same structure can also exhibit different configurations, where they may exist as non-superimposable mirror images, or groups of atoms may be held in different spatial arrangements on either side of a rigid carbon-carbon double bond. This concept may be difficult to envisage, but is crucially important in drug design, as will be seen later in the text. For example, the unfortunate consequences of thalidomide, used for morning sickness, was due to the drug been administered as a fifty-fifty mixture of the mirror images, where one of the spatial arrangements caused harm.
Assigning confidence to molecular property prediction
Published in Expert Opinion on Drug Discovery, 2021
AkshatKumar Nigam, Robert Pollice, Matthew F. D. Hurley, Riley J. Hickman, Matteo Aldeghi, Naruki Yoshikawa, Seyone Chithrananda, Vincent A. Voelz, Alán Aspuru-Guzik
Another important and often underappreciated source of uncertainty, especially in complex systems, are the input features. This is particularly true for chemistry where molecular properties are generally conformer-dependent, and most molecules adopt much more than just one conformation under ambient conditions. Data-driven models, in contrast, are largely trained on 2D molecular representations that neglect conformations entirely. Accordingly, incorporating 3D structures and appropriate features in ML models is an active field of research. The main challenge is to offset the added cost of generating representative 3D conformations with higher prediction accuracy in the final models. Currently, 2D molecular representations are still the state of the art in the field but we believe 3D features will become the standard in the near future. Notably, this is also related to the so-called activity cliffs, the observation that small structural modifications can lead to large changes in activities[126]. When the input features cannot capture these activity cliffs properly the resulting data-driven models will likely fail to predict them. However, when the input features are appropriate, the apparent activity cliff should disappear in that feature space.
Emerging role of metabolomics in protein conformational disorders
Published in Expert Review of Proteomics, 2021
Nimisha Gupta, Sreelakshmi Ramakrishnan, Saima Wajid
Metabolomics has gradually become an impressive and encouraging tool for identifying biomarkers and understanding the molecular basis of the pathogenesis of diseases. It plays a key role in finding alterations in protein conformational changes in relation to diseases. In this review, we have summarized the metabolomic studies aimed at the characterization of metabolite alterations that result in functional and expressional changes using samples such as plasma/serum, cerebrospinal fluid, and other biofluids of human patients/ animal models. These studies have helped in the analysis of different systematic alterations in various disease types; protein conformational diseases being one of these categories. In protein conformational diseases, aggregates are formed as the result of protein misfolding. These aggregations later lead to small or large variations in the concentration of metabolites present in the system, causing dysregulation of essential pathways and changing functional and expressional metabolism. Moreover, metabolomic analysis has provided proof of alterations in metabolites that induce disease progression.
Synthesis and evaluation of novel benzimidazole derivatives as potential anti bacterial and anti fungal agents
Published in Egyptian Journal of Basic and Applied Sciences, 2021
Vishwajeet Amarsingh Pardeshi, Sultan Pathan, Amit Bhargava, Narendra Singh Chundawat, Girdhar Pal Singh
Molecular modeling studies has constantly been proven to be a robust tool for justifying and ranking the conformations using a scoring function and also helps in finding the interactions for making this information available to virtual screening techniques. In addition, it also helps us to propose structural hypotheses of how the ligand inhibits the target. The enzymatic database that was developed from the total set of compounds was docked into the certain binding province. Molecular docking was achieved using the Surflex-Dock program that is associated with Sybyl-X 2.0 [31]. The crystal structure of Cytochrome P450 14 alpha-sterol demethylase (CYP51) from Mycobacterium tuberculosis in composite with fluconazole was collected from PDB under code 1EA1 (X-Ray Diffraction; 2.21 Å) [32] and was extracted from the Brookhaven Protein Database (PDB: http://www.rcsb.org/pdb). The file was prepared for docking by adding a polar hydrogen atom with MMFF94 charges and water molecules were removed. The 3D structure of ligand, which was produced by the SKETCH module complies with the SYBYL application (Tripos Inc., St. Louis, USA) in addition its energy-reduced confirmation was acquired with the assistance of Tripos force field by using MMFF94 [1] charges and molecular docking was achieved with Surflex-Dock program that is interfaced with Sybyl-X 2.0 and other miscellaneous parameters were allocated with default figures stated by the software.