Small Molecule Crystallography in Drug Design

Ooms, Frédéric

doi:10.2174/1381612013397889

Cited by 13 publications

(5 citation statements)

References 69 publications

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“…Using the structures of drugs to map receptor binding sites is a useful approach (see for example [189] in this journal). Three-dimensional structures are available for several hypoglycemic compounds including glibenclamide [190], glimerperide, and repaglinide [149].…”

Section: An Unexpected Source Of Structural Insightmentioning

confidence: 99%

Insulin Secretagogues, Sulfonylurea Receptors and KATP Channels

Bryan¹,

Crane²,

Vila-Carriles³

et al. 2005

CPD

118

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ATP-sensitive K+ channels, termed K(ATP) channels, provide a link between cellular metabolism and membrane electrical activity in a variety of tissues. Channel isoforms have been identified and are targets for compounds that both stimulate and inhibit their activity resulting in membrane hyperpolarization and depolarization, respectively. Examples include relaxation of vascular smooth muscle and stimulation of insulin secretion. This article reviews the cloning, molecular biology, and structure of K(ATP) channels, with particular focus on the SUR1/K(IR)6.2 neuroendocrine channels that are important for the regulation of insulin secretion. We integrate the extensive pharmacologic structure-activity-relationship data on these channels, which defines a bipartite drug binding pocket in the SUR (sulfonylurea receptor), with recent structure-function studies that identify domains of SUR and K(IR)6.2, the channel pore, which are critical for channel assembly, for gating, and for the ligand-receptor interactions that modulate channel activity. The atomic structure of a sulfonylurea in a protein pocket is used to develop insight into the recognition of these compounds. A homology model of K(ATP) channels, based on VC-MsbA, another member of the ABC protein family, is described and used to position amino acids important for the action of channel openers and blockers within the core of SUR. The model has a central chamber which could serve as a multifaceted binding pocket.

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Section: An Unexpected Source Of Structural Insightmentioning

confidence: 99%

Insulin Secretagogues, Sulfonylurea Receptors and KATP Channels

Bryan¹,

Crane²,

Vila-Carriles³

et al. 2005

CPD

118

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“…X-ray crystallography is the primary method for determining the absolute configuration of a molecule and results from crystallographic studies provide unambiguous, accurate, and reliable 3-dimensional structural parameters, which are prerequisites for rational drug design and structure-based functional studies. Thus the role of crystallography in drug design is widely recognized (Cachau and Podjarny, 2005; Deschamps, 2005; Williams et al, 2005; Blundell et al, 2002; Wouters and Ooms, 2001). …”

Section: Introductionmentioning

confidence: 99%

X-ray crystallography of chemical compounds

Deschamps

2010

Life Sciences

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Aims-Accurate knowledge of molecular structure is a prerequisite for rational drug design. This review examines the role of x-ray crystallography in providing the required structural information and advances in the field of x-ray crystallography that enhance or expand its role.Main Methods-X-ray crystallography of new drugs candidates and intermediates can provide valuable information of new syntheses and parameters for quantitative structure activity relationships (QSAR).Key Findings-Crystallographic studies play a vital role in many disciplines including materials science, chemistry, pharmacology, and molecular biology. X-ray crystallography is the most comprehensive technique available to determine molecular structure. A requirement for the high accuracy of crystallographic structures is that a 'good crystal' must be found, and this is often the rate-limiting step. In the past three decades developments in detectors, increases in computer power, and powerful graphics capabilities have contributed to a dramatic increase in the number of materials characterized by x-ray crystallography. More recently the advent of high-throughput crystallization techniques has enhanced our ability to produce that one good crystal required for crystallographic analysis.Significance-Continuing advances in all phases of a crystallographic study have expanded the ranges of samples which can be analyzes by x-ray crystallography to include larger molecules, smaller or weakly diffracting crystals, and twinned crystals.

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“…One of the critical steps in rational drug design is obtaining knowledge of the structure of the new drug candidates, and single-crystal X-ray diffraction (SCXD) is one of the most powerful methods for gaining this fundamental information, which can be used to guide the drug-design studies in connection with other technologies such as pharmacophore model elaborations, 3D QSAR, docking, and de novo design. SCXD has thus become an essential tool for drug development to unambiguously determine the threedimensional structures of molecules, which eventually paves the way for rapid development of new molecules (Wouters & Ooms, 2001). Moreover, during the drug-development process, another important issue lies in understanding the crystal packing of the active pharmaceutical ingredient (drug substance) for suitable formulation development.…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure and Hirshfeld surface analysis of 4-(4-chlorophenyl)-5-methyl-3-{4-[(2-methylphenyl)methoxy]phenyl}-1,2-oxazole

Aydın¹,

Akkurt²,

Turanlı³

et al. 2021

Acta Cryst E

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In the title compound, C24H20ClNO2, the mean planes of 4-chlorophenyl, 2-methylphenyl and phenylene rings make dihedral angles of 62.8 (2), 65.1 (3) and 15.1 (2)°, respectively, with the 5-methyl-1,2-oxazole ring. In the crystal, molecules are linked by intermolecular C—H...N, C—H...Cl, C—H...π contacts and π–π stacking interactions between the phenylene groups. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H...H (48.7%), H...C/C...H (22.2%), Cl...H/H...Cl (8.8%), H...O/O...H (8.2%) and H...N/N...H (5.1%) interactions.

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Small Molecule Crystallography in Drug Design

Cited by 13 publications

References 69 publications

Insulin Secretagogues, Sulfonylurea Receptors and KATP Channels

Insulin Secretagogues, Sulfonylurea Receptors and KATP Channels

X-ray crystallography of chemical compounds

Crystal structure and Hirshfeld surface analysis of 4-(4-chlorophenyl)-5-methyl-3-{4-[(2-methylphenyl)methoxy]phenyl}-1,2-oxazole

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