The Crystal Structure of Insulin

Clark, George L.; Corrigan, K. E.

doi:10.1103/physrev.40.639

Cited by 15 publications

(3 citation statements)

References 4 publications

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“…Examples of fragment-based ligand/lead discovery (FBLD)-derived drugs/compounds (adapted from [35]). Compounds for which the corresponding clinical phase has failed or has been discontinued; 2 Compounds whose development status is unknown; 3 In October 2018, at least nineteen fragment-based ligand/lead discovery (FBLD)-derived drugs were in Phase I.…”

Section: Soakingmentioning

confidence: 99%

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Protein X-ray Crystallography and Drug Discovery

2020

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With the advent of structural biology in the drug discovery process, medicinal chemists gained the opportunity to use detailed structural information in order to progress screening hits into leads or drug candidates. X-ray crystallography has proven to be an invaluable tool in this respect, as it is able to provide exquisitely comprehensive structural information about the interaction of a ligand with a pharmacological target. As fragment-based drug discovery emerged in the recent years, X-ray crystallography has also become a powerful screening technology, able to provide structural information on complexes involving low-molecular weight compounds, despite weak binding affinities. Given the low numbers of compounds needed in a fragment library, compared to the hundreds of thousand usually present in drug-like compound libraries, it now becomes feasible to screen a whole fragment library using X-ray crystallography, providing a wealth of structural details that will fuel the fragment to drug process. Here, we review theoretical and practical aspects as well as the pros and cons of using X-ray crystallography in the drug discovery process.

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Section: Soakingmentioning

confidence: 99%

“…The first X-ray diffraction by protein crystals was reported in the early thirties [1,2], but nearly 30 years passed before the atomic crystallographic structure of myoglobin was published [3]. Yet, the potential of X-ray crystallography was already evidenced as it allowed the unambiguous structure determination of penicillin [4].…”

Section: Introductionmentioning

confidence: 99%

Protein X-ray Crystallography and Drug Discovery

2020

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“…SCXRD has historically been the most sought-after technique for the determination of several structural features in drug molecules and has played a major role in structure-based drug design (SBDD), drug-receptor interactions, and the development of target biomolecule-ligand complexes. The first hexagonal bipyramidal structure of pepsin was prepared by Dr. Philpot in the lab of Dr. Theodor Svedberg in Uppsala and studied by Dr. Bernal, also known as Sage in the early 1930s during his position at Cambridge [ 3 , 4 ]. About 28 years later, Dr. John Kendrew (1958) and Dr. Max Perutz (1960) were awarded the Nobel Prize in Chemistry (1962) for determining the crystal structure of myoglobin and hemoglobin, respectively [ 5 ].…”

Section: Significance Of X-ray Crystallography In Drug Discoverymentioning

confidence: 99%

Using X-ray Diffraction Techniques for Biomimetic Drug Development, Formulation, and Polymorphic Characterization

2020

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Drug development is a decades-long, multibillion dollar investment that often limits itself. To decrease the time to drug approval, efforts are focused on drug targets and drug formulation for optimal biocompatibility and efficacy. X-ray structural characterization approaches have catalyzed the drug discovery and design process. Single crystal X-ray diffraction (SCXRD) reveals important structural details and molecular interactions for the manifestation of a disease or for therapeutic effect. Powder X-ray diffraction (PXRD) has provided a method to determine the different phases, purity, and stability of biological drug compounds that possess crystallinity. Recently, synchrotron sources have enabled wider access to the study of noncrystalline or amorphous solids. One valuable technique employed to determine atomic arrangements and local atom ordering of amorphous materials is the pair distribution function (PDF). PDF has been used in the study of amorphous solid dispersions (ASDs). ASDs are made up of an active pharmaceutical ingredient (API) within a drug dispersed at the molecular level in an amorphous polymeric carrier. This information is vital for appropriate formulation of a drug for stability, administration, and efficacy purposes. Natural or biomimetic products are often used as the API or the formulation agent. This review profiles the deep insights that X-ray structural techniques and associated analytical methods can offer in the development of a drug.

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Low‐angle scattering in polymers

Kratky

1948

J. Polym. Sci.

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The diffraction of x‐rays at small angles occurs in the form of sharp interferences (discontinuous) or as diffuse scattering (continuous). The first effect is observed mostly in crystallized proteins and in protein fibers. New measurements on collagen were obtained by the author in collaboration with Sekora, and independently by Bear. Using these data, an attempt has been made to establish a connection between the orders of the intense reflections belonging to the giant period of 642 Å. along the fiber axis and the frequency of the amino acid residues (frequency is defined as the number of amino acid residues of a particular kind among the total 220 residues which constitute the basic period of 642 Å. along the fiber axis). With the exception of the most abundant amino acids, glycine and proline, it is possible to assign to each frequency a corresponding reflection, and vice versa. This indicates a high degree of regularity in the arrangement of these amino acid residues. But the relationships are apparently more complex than would be expected from the Bergmann‐Niemann rule. For example, the frequencies of 11 and 20 (corresponding to an identical residue at each 220/11 or 20th location or at each 220/20 or 11th location, respectively) appear to play a role. Fundamentally, however, we arrive at a picture in accordance with the comprehensive investigations and results of Astbury. It has not yet been possible to arrive at a detailed structure.In the theory of diffuse low‐angle scattering, it is necessary to distinguish between densely packed systems and dilute systems. For the latter case, molecular scattering is computed in accordance with Debye's theory of scattering. It is shown how size factor and form factor may be separated. Both of these properties can be approximated without making previous assumptions, though the accuracy of the form factor determination can be improved appreciably if the particle weight is known. Preliminary trial measurements on solutions of edestin, tobacco mosaic virus, and hemocyanin are in agreement for the first two substances mentioned. The measurements on insulin indicate associated particles that deviate strongly from spherical shape (however, these measurements were made at an earlier date and require checking). Those on hemocyanin indicate an association similar to a string of pearls, a result which probably explains the contradiction of the substance appearing as spherical particles under the electron microscope, while exhibiting flow birefringence when in solution. When this method is developed further it will undoubtedly become a valuable tool for the determination of form and size of polymer molecules and other colloidal particles.

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The Crystal Structure of Insulin

Cited by 15 publications

References 4 publications

Protein X-ray Crystallography and Drug Discovery

Protein X-ray Crystallography and Drug Discovery

Using X-ray Diffraction Techniques for Biomimetic Drug Development, Formulation, and Polymorphic Characterization

Low‐angle scattering in polymers

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