| 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. |
