J. Appl. Cryst.の発刊に際して

It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.

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Fluorine in medicinal chemistry.

The Cationminus signpi Interaction.

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

Applications of Fluorine in Medicinal Chemistry

Enzymes synthesized by hyperthermophiles (bacteria and archaea with optimal growth temperatures of >80°C), also called hyperthermophilic enzymes, are typically thermostable (i.e., resistant to irreversible inactivation at high temperatures) and are optimally active at high temperatures. These enzymes share the same catalytic mechanisms with their mesophilic counterparts. When cloned and expressed in mesophilic hosts, hyperthermophilic enzymes usually retain their thermal properties, indicating that these properties are genetically encoded. Sequence alignments, amino acid content comparisons, crystal structure comparisons, and mutagenesis experiments indicate that hyperthermophilic enzymes are, indeed, very similar to their mesophilic homologues. No single mechanism is responsible for the remarkable stability of hyperthermophilic enzymes. Increased thermostability must be found, instead, in a small number of highly specific alterations that often do not obey any obvious traffic rules. After briefly discussing the diversity of hyperthermophilic organisms, this review concentrates on the remarkable thermostability of their enzymes. The biochemical and molecular properties of hyperthermophilic enzymes are described. Mechanisms responsible for protein inactivation are reviewed. The molecular mechanisms involved in protein thermostabilization are discussed, including ion pairs, hydrogen bonds, hydrophobic interactions, disulfide bridges, packing, decrease of the entropy of unfolding, and intersubunit interactions. Finally, current uses and potential applications of thermophilic and hyperthermophilic enzymes as research reagents and as catalysts for industrial processes are described.

Hyperthermophilic Enzymes: Sources, Uses, and Molecular Mechanisms for Thermostability

The present invention relates to a polypeptide binding to a chymase (EC 3.4.21.39), wherein the polypeptide comprises or consists of an amino acid sequence selected from the group consisting of: (a) GVTLFVALYDY(X 1 )A(X 2 )(X 3 )(X 4 )(X 5 )(X 6 )LSFHKGEKFQIL(X 1 )(X 8 )(X 9 )(X 10 )(X 11 )(X 12 )G(X 13 )(X 14 )WEARS LTTGETGYIPSNYVAPVDSIQ (SEQ ID NO: 1), wherein (X 1 ) is R, N, Q, E, K, H, S, T, C, or D; (X 2 ) is E, T, D, Q, L, P, A, S, C, M, N, E, G, A, V or I; (X 3 ) is R, T, H, N, K, S, C, N or Q; (X 4 ) is S, W, T, C, N, Q, F or Y; (X 5 ) is T, H, L, F, C, S, M, N, Q, R, K, G, A, V, I, P, Y or W; (X 6 ) is D, Q, H, E, S, T, C, N, R or K; (X 7 ) is D, N, R, E, Q, S, T, C, K or D; (X 8 ) is M, W, G, F, A, S, T, C, S, N, Q, Y, V, L, I or P; (X 9 ) is T, H, S, D, C, N, Q, R, K, E or absent; (X 10 ) is V, T, Q, G, A, L, I, P, S, C, M, N or absent; (X 11 ) is P, A, D, G, K, V, L, I, E, R, M, H or absent; (X 12 ) is N, V, P, I, E, T, S, A, G, L, C, M, Q or D; (X 13 ) is D, E, T, P, G, A, V, L, I, S, C, M, N or Q, and (X 14 ) is W, Y, L, G, A, V, I, P, M, or F; (b) an amino acid sequence which is at least 85% identical to the amino acid sequence of (a), wherein the identity determination excludes amino acid positions (X 1 ) to (X 14 ).

New chymase binding compounds and medical uses thereof

A method for transmission mode X-ray diffraction analysis of a sample by means of an apparatus comprising an X-Ray radiation source (21) that provides X-ray radiation for irradiating the sample and a detector (22) for detecting X-ray radiation transmitted through and diffracted by the sample. The method comprises: (a) placing a sample to be analyzed on a substrate (19), (b) generating a strip-shaped X-ray beam (24) the central part of which extends along a plane, (c) positioning the substrate (19) and thereby the sample in an initial position in which said sample lies in the path of beam (24) and a slice (27) of the sample is irradiated by beam (24), (d) effecting the following movements of the substrate (19) with respect to the above mentioned initial position thereof: (d.1) a rotation of the substrate (19) and thereby of the sample around a rotation axis (29) which is perpendicular to the substrate, the rotation covering a predetermined rotation angle, and (d.2) a tilting of the substrate (19) and thereby of the sample around a tilting axis (28) and over a tilting angle (T) defined as the angle that the rotation axis (29) forms with the plane through which the central part of the beam (24) extends, the tilting axis lying in the plane through which the central part of the beam (24) extends and being perpendicular to the rotation axis (29), the tilting covering a tilting angle (T) that varies between a first predetermined value and a second predetermined value, and (e) detecting with the detector (22) X-ray radiation transmitted through and diffracted by the sample during a time interval over which the above mentioned movements of the substrate (19) are effected.

Method and apparatus for x-ray diffraction analysis

The in meso in situ serial X-ray crystallization method (Huang et al., (2015) Acta Crystallogr D Biol Crystallogr 71, 1238) combines lipid cubic phase crystallization, direct freezing of the crystallization droplet without handling of the crystals, and data collection in situ. Recently, this method was used to overcome the mechanical fragility of crystals which enabled the X-ray structure determination of chemokine receptor 2A (Apel et al., (2019) Structure 27, 427) at 2.7 A resolution. The CCR2 structure provides the structural basis for ligand selectivity of CCR2 against chemokine receptor 5 and provides insights into the residence time of MK-0812 analogs based on molecular dynamics simulations. These findings offer new opportunities for drug discovery targeting chemokine receptors.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.15098

In situ crystallography as an emerging method for structure solution of membrane proteins: the case of CCR2A

The carbohydrate nitro enone 1 was found to react with amines to give α-ketene ketals; the formation of carbohydrate azo derivatives could be suppressed by addition of an electron-rich aniline quenching agent. Upon reaction with benzaldehyde in the presence of trifluoroacetic acid, the α-oxoketene ketals afforded dihydroquinolines in a cyclization reaction forming two new carbon–carbon bonds. For the dihydroquinoline 18 the newly formed stereocenter was ascertained by X-ray crystallography. The two-step reaction could be carried out as one multicomponent reaction. Electron-poor anilines led to Hantzsch-type products incorporating two enaminone molecules; the crystal structure of representative 30 is reported.

Carbohydrate α-oxoketene N,O-ketals in the synthesis of dihydroquinolines

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Michael Hennig

Papers

New chymase binding compounds and medical uses thereof

Method and apparatus for x-ray diffraction analysis

In situ crystallography as an emerging method for structure solution of membrane proteins: the case of CCR2A

Carbohydrate α-oxoketene N,O-ketals in the synthesis of dihydroquinolines

X-ray free-electron laser: opportunities for drug discovery