LitCovid-sentences  

PMC:7594251 / 1731-7671 JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T16 0-2 Sentence denotes 1.
T17 3-15 Sentence denotes Introduction
T18 16-112 Sentence denotes The unexpected SARS-CoV-2/COVID-19 outbreak, with over 34 million confirmed cases globally (Oct.
T19 113-299 Sentence denotes 2020) and the struggle for survival in the absence of a proven and efficient treatments, emphasizes the critical need to develop effective, novel, and rapid drug discovery methodologies.
T20 300-434 Sentence denotes Even though the pharmaceutical industry works constantly to discover and develop novel drugs, the process is still slow and expensive.
T21 435-588 Sentence denotes The cost of introducing a new drug has increased steadily, with current cost estimates predicting that a future drug will cost in excess of $2.6 billion.
T22 589-743 Sentence denotes The typical development cost is usually spread out over the course of 14 years [1,2,3], making investment even more difficult (i.e., cost recovery delay).
T23 744-915 Sentence denotes This high investment barrier for drug development is a result of numerous testing phases (Scheme 1), with each phase requiring a statistically significant number of cases.
T24 916-1079 Sentence denotes Although there are several other substantial costs to drug development, that discussion of experimental methods to reduce costs is beyond the scope of this review.
T25 1080-1234 Sentence denotes The emergence of a pandemic and the emergencies it creates worldwide understandably drive and motivate the rapid development and/or optimization of drugs.
T26 1235-1319 Sentence denotes However, patient safety and subsequent earned public trust is a primary requirement.
T27 1320-1575 Sentence denotes Drug redirecting/repurposing (Scheme 1) is an efficient short-cut method in disease treatment that utilizes existing tools, and combines artificial intelligence, machine learning algorithms, and experimental NMR techniques (i.e., “from Bench to Bedside”).
T28 1576-1687 Sentence denotes This process must be relatively rapid and efficient to have any benefit to patients and the health-care system.
T29 1688-1873 Sentence denotes Compared to mass spectrometry and high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) is another powerful technique with several unique advantages [5,6,7,8].
T30 1874-2074 Sentence denotes NMR is intrinsically quantitative, and it provides several different approaches that are routinely utilized to identify and structurally elucidate molecules of interest [9,10,11,12,13,14,15,16,17,18].
T31 2075-2388 Sentence denotes In contrast to mass spectrometry, NMR is non-destructive, non-invasive, has extremely high reproducibility permitting researchers to acquire measurements under different experimental conditions (e.g., temperature, time points, and concentrations) often while the same sample is inside the magnet [19,20,21,22,23].
T32 2389-2572 Sentence denotes NMR can be used in reaction kinetic studies while several consecutive measurements are taken, and while spectral changes (function of the reaction time) are analyzed [24,25,26,27,28].
T33 2573-2636 Sentence denotes Moreover, molecules are studied at the atomic level [29,30,31].
T34 2637-2847 Sentence denotes Unlike other analytical tools, NMR provides dynamic information, and NMR experiments can be carried out under physiological conditions (e.g., atmospheric pressure, temperature, and different pH values) [32,33].
T35 2848-2991 Sentence denotes This is especially important in medical drug design since one must understand the interactions between an enzyme of interest and the ligand(s).
T36 2992-3162 Sentence denotes NMR provides information on the binding affinity of such ligands, details/location of the binding site, and associated structural changes following binding [32,33,34,35].
T37 3163-3292 Sentence denotes These biophysical details are essential when evaluating the potential efficacy of a drug, and during any subsequent optimization.
T38 3293-3390 Sentence denotes The available literature [32,33,34,36] highlights the practicality of NMR in drug design studies.
T39 3391-3606 Sentence denotes For these reasons, NMR spectroscopy is highly sought after in drug development [37,38,39,40,41], for both molecule identification [11,13,14,18,42,43,44,45,46] and structural elucidation [15,16,17,45,47,48,49,50,51].
T40 3607-3822 Sentence denotes NMR has been successfully applied in stereochemistry [52,53,54,55,56] and isomer determination [57,58,59,60,61], in drug-protein interactions studies [62,63,64], and in the evaluation of drug toxicity [65,66,67,68].
T41 3823-3953 Sentence denotes The use of NMR in drug design is not restricted to academic laboratories and gained interest from those in development industries.
T42 3954-4077 Sentence denotes The use of NMR in drug development increased in the late ‘80s, as seen in both scientific and patent literature (Figure 1).
T43 4078-4193 Sentence denotes While scientific interest in NMR is still growing, the number of patents has been decreasing since the early 2000s.
T44 4194-4341 Sentence denotes The top applicants of NMR in pharmaceutical patents are Bristol Myers, AstraZeneca, and Wyeth, with 146, 104, and 67 patent families, respectively.
T45 4342-4497 Sentence denotes In addition to the advantages provided by NMR, it is often used with complementary methods such as X-ray crystallography, HPLC, and mass spectrometry [69].
T46 4498-4705 Sentence denotes An example of this is found in work by Wyss et al. [36], where they combined X-ray crystallography with NMR fragment-based screening to create the first inhibitor candidate for BACE-1 in Alzheimer’s disease.
T47 4706-4891 Sentence denotes BACE-1 is a membrane-anchored aspartic acid protease and is responsible for the production of amyloid beta peptides in neurons related to the progression of Alzheimer’s disease [36,70].
T48 4892-5106 Sentence denotes Using NMR fragment-based screening, Wyss et al. identified isothiourea as binding to BACE-1 and confirmed this observation with the X-ray crystal structure of the complex of a ligand-efficient isothiourea fragment.
T49 5107-5256 Sentence denotes Information obtained from these experiments aided in design optimization, resulting in the selection of iminopyrimidinones as BACE-1 inhibitors [36].
T50 5257-5355 Sentence denotes This is a perfect example of using different complementary methods to maximize scientific outcome.
T51 5356-5453 Sentence denotes However, in order to be efficient, one must know the advantages and disadvantages of each method.
T52 5454-5578 Sentence denotes One of the major issues regarding NMR is the effective size restriction when measuring targets such as proteins above 40kDa.
T53 5579-5782 Sentence denotes Recent progress has extended this mass limit; an example of this is the resolved structure of chaperone SecB in complex with unstructured proPhoA (PDB ID 5JTL) with a total mass of 119kDa using NMR [71].
T54 5783-5940 Sentence denotes In this review, we present practical guideline to use NMR techniques in drug design studies and provide examples of the successful use of NMR in drug-design.