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PMC:7594251 / 71812-76782 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T479 0-4 Sentence denotes 3.3.
T480 5-45 Sentence denotes Paramagnetic Resonance in Drug Discovery
T481 46-260 Sentence denotes Paramagnetic NMR (PNMR) can also play a prominent role in drug discovery [341], as PNMR can provide key structural information in situations where crystal structures cannot due to the weak binding of ligands [341].
T482 261-378 Sentence denotes PNMR can be used to quantify the binding between ligands and large biomolecules such as proteins, DNA, and RNA [342].
T483 379-665 Sentence denotes PNMR depends on the presence of a group (called the paramagnetic center) with an unpaired electron [343], and since many naturally occurring biomolecules and organic compounds lack a paramagnetic center, one such as caged lanthanide (CLaNP) [344], must be introduced artificially [341].
T484 666-851 Sentence denotes Once the paramagnetic center (often a metal ion) is present, paramagnetic effects can be used to measure the distance and the relative orientation (i.e., angle) between molecules [345].
T485 852-941 Sentence denotes This information is crucial when it comes to determining how ligands and substrates bind.
T486 942-1038 Sentence denotes Thus, PNMR is quite a useful technique for drug discovery when a paramagnetic center is present.
T487 1039-1272 Sentence denotes The most relevant consequence of PNMR for drug discovery is paramagnetic relaxation enhancement (PRE), although there are a number of studies demonstrating the use of pseudocontact shift (PCS) effect in drug discovery research [341].
T488 1273-1516 Sentence denotes Paramagnetic relaxation enhancement (PRE) is proportional to the inverse sixth power of the distance between the paramagnetic center and the nucleus of interest (i.e., 1H), although it does not reveal anything about relative orientation [341].
T489 1517-1593 Sentence denotes PRE can give quantitative information in the range of 10–25 Angstroms [346].
T490 1594-1781 Sentence denotes Several researchers have taken advantage of this outstanding property to study the structural and dynamic properties of complex biomolecular machineries in their native environment [347].
T491 1782-2137 Sentence denotes For example, Iwahara et al. (2003) demonstrated that a protein’s binding polarity to DNA can be determined by PRE, using EDTA-derivatized deoxythymidine (dT-EDTA) with a chelated metal ion (such as Cu2+ or Mn2+) as a probe. dT-EDTA with a chelated metal ion is a convenient choice, as it can be inserted into any position of a synthesized oligonucleotide.
T492 2138-2261 Sentence denotes With data derived from the PRE effect, one can easily determine the polarity of the protein (or drug) binding to DNA [348].
T493 2262-2569 Sentence denotes Several researchers have investigated DNA as a drug target [349], and the study of Iwahara et al. clearly demonstrates, and even indicates, that PRE can potentially be used to study the interactions between a drug and DNA [348], provided that a paramagnetic center such as dT-EDTA or a metal ion is present.
T494 2570-2678 Sentence denotes Brasuń et al. [350] also used PRE derived distances between a paramagnetic center and a nucleus of interest.
T495 2679-2859 Sentence denotes They replaced the Cys-S-S-Cys bridge found in oxytocin and vasopressin with the His-Cu2+-His motif to investigate if doing so would alter the stability of oxytocin and vasopressin.
T496 2860-3071 Sentence denotes They determined the distances between the Cu2+ ion and 1H nuclei (possible because of PRE), and used these values to generate three-dimensional models of the His-Cu2+-His motifs in both oxytocin and vasopressin.
T497 3072-3394 Sentence denotes In doing so, they indicated that such an approach using PRE can help in designing new biologically active compounds [350], and hence in drug discovery research, as many drug discovery studies require a reliable models for the successful generations of hit-lead molecules, especially in the case of in silico docking [351].
T498 3395-3490 Sentence denotes This study again proves the usefulness of PRE, and therefore, PNMR, in drug discovery research.
T499 3491-3632 Sentence denotes In two additional studies, Huang et al. [352,353] used PRE in their individual studies of protein binding and protein dynamics, respectively.
T500 3633-3796 Sentence denotes In the Huang et al. case [352], these authors used PRE to establish a model of the binding between the G-actin protein, and thymosin β4, an actin- binding protein.
T501 3797-3965 Sentence denotes Using PRE determined constraints (distances) and 1H-15N HSQC, they were able to establish a well-converging docking structure of the G-actin/thymonsin β4 complex [352].
T502 3966-4190 Sentence denotes On the other hand Huang et al. [353] did not measure protein binding, but studied the conformational changes and dynamics of select large membrane proteins utilizing 19F-NMR spectroscopy, and Ni2+ as the paramagnetic center.
T503 4191-4706 Sentence denotes Through a series of extensive experiments, they showed that conformational exchange rates of membrane proteins can be determined from measurements of the metal-enhanced longitudinal relaxation (i.e., PRE) of the 19F nuclei [353], thus yielding additional information (i.e., protein conformation dynamics) that could be utilized in drug discovery projects targeting proteins (i.e., understanding how the protein changes shape based on its environment can be used to find potential binding sites for drug candidates).
T504 4707-4970 Sentence denotes All these examples prove that PNMR is powerful approach in drug discovery research, given that PRE can aid in generating trustworthy models of interacting molecules, and that it can help researchers understand better how the molecules interact in the first place.