Validating and Understanding Ring Conformations Using Small Molecule Crystallographic Data

Cottrell, Simon J.; Olsson, Tjelvar S. G.; Taylor, Robin; Cole, Jason C.; Liebeschuetz, John W.

doi:10.1021/ci200439d

Cited by 49 publications

(51 citation statements)

References 44 publications

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“…[6,7] Some reports suggest to set the threshold for the bioactive conformation at 3kcal mol À1 of the loweste nergy conformation, [6,8] whereas others give am aximum Gibbs energy differenceo f5kcal mol À1 . [17] Herein, we report two new series of ligandsbased on apyrazolopyran core that inhibitt he enzyme serine hydroxymethyltransferase( SHMT) and analyze how their molecular conformations profoundly affect bindingg eometry and biological activity.T his enzymei sacrucial component of the folate synthesis cycle, [18,19] which is an essential pathway for the replication of Plasmodium parasites causingm alaria. [15,16] The potential of conformationals earchesi nt he CSD was nicely illustrated by Brameld et al, [7] who reported ac omprehensive study on most of the structuralm otifs used in medicinal chemistry.…”

Section: Introductionmentioning

confidence: 99%

Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs

Schwertz

Frei

Witschel

et al. 2017

Chemistry A European J

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Malaria remains a major threat to mankind due to the perpetual emergence of resistance against marketed drugs. Twenty-one pyrazolopyran-based inhibitors bearing terminal biphenyl, aryl sulfonamide, or aryl sulfone motifs were synthesized and tested towards serine hydroxymethyltransferase (SHMT), a key enzyme of the folate cycle. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target, as well as PfNF54 strains in cell-based assays in the low nanomolar range (18-56 nm). Seven co-crystal structures with P. vivax (Pv) SHMT were solved at 2.2-2.6 Å resolution. We observed an unprecedented influence of the torsion angle of ortho-substituted biphenyl moieties on cell-based efficacy. The peculiar lipophilic character of the sulfonyl moiety was highlighted in the complexes with aryl sulfonamide analogues, which bind in their preferred staggered orientation. The results are discussed within the context of conformational preferences in the ligands.

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Section: Introductionmentioning

confidence: 99%

Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs

Schwertz

Frei

Witschel

et al. 2017

Chemistry A European J

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“…This process resulted in 284 potential ligands, further evaluated using interactive graphics and MOGUL, which uses information from the Cambridge Structural Database (CSD) to assess ligand geometries. 36 Binding poses with highly unusual or unlikely torsion angle and ring geometries were manually removed from the hit set intended for Please do not adjust margins Please do not adjust margins biophysical screening. In addition, chemically similar hits were removed in order to reduce redundancies.…”

Section: Selection Of Virtual Screening Hits -mentioning

confidence: 99%

New active leads for tuberculosis booster drugs by structure-based drug discovery

Tatum

Liebeschuetz²,

Cole

et al. 2017

Org. Biomol. Chem.

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The transcriptional repressor EthR from Mycobacterium tuberculosis, a member of the TetR family of prokaryotic homo-dimeric transcription factors, controls the expression of the mycobacterial mono-oxygenase EthA. EthA is responsible for the bio-activation of the second-line tuberculosis pro-drug ethionamide, and consequently EthR inhibitors boost drug efficacy. Here, we present a comprehensive in silico structure-based screening protocol that led to the identification of a number of novel scaffolds of EthR inhibitors in subsequent biophysical screening by thermal shift assay. Growth inhibition assays demonstrated that five of the twenty biophysical hits were capable of boosting ethionamide activity in vitro, with the best novel scaffold displaying an EC of 34 μM. In addition, the co-crystal structures of EthR with four new ligands at resolution ranging from 2.1 to 1.4 Å confirm the binding and inactivation mode, and will enable future lead development.

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“…By improving this technology, it will be possible to use it quantitatively to assess 'hot spots' of interactions to recognise pharmacophores or chemophores. The CSD System also developed the two extensive knowledge bases Mogul 17,18 and IsoStar. 16 Mogul comprises more than 20 million bond lengths, valence and torsion angles organised into more than 11.5 million chemically searchable distributions, each relating to a specific chemical environment, revealing also data for chemical rings.…”

Section: 14mentioning

confidence: 99%

Fiftieth Anniversary of the Cambridge Structural Database and Thirty Years of Its Use in Croatia

Kojić‐Prodić

Molčanov

2015

Kem. Ind.

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This article is dedicated to the memory of Dr. F. H. Allen and the 50 th anniversary of the Cambridge Crystallographic Data Centre (CCDC); the world-renowned centre for deposition and control of crystallographic data including atomic coordinates that define the three-dimensional structures of organic molecules and metal complexes containing organic ligands. The mission exposed at the web site (http://www.ccdc.cam.ac.uk) is clearly stated: "The Cambridge Crystallographic Data Centre (CCDC) is dedicated to the advancement of chemistry and crystallography for the public benefit through providing high quality information, software and services." The Cambridge Structural Database (CSD), one among the first established electronic databases, nowadays is one of the most significant crystallographic databases in the world. In the International Year of Crystallography 2014, the CSD announced in December over 750,000 deposited structures. The use of the extensive and rapidly growing database needs support of sophisticated and efficient software for checking, searching, analysing, and visualising structural data. The seminal role of the CSD in researches related to crystallography, chemistry, materials science, solid state physics and chemistry, (bio)technology, life sciences, and pharmacology is widely known. The important issues of the CCDC are the accuracy of deposited data and development of software for checking the data. Therefore, the Crystallographic Information File (CIF) is introduced as the standard text file format for representing crystallographic information. Among the most important software for users is ConQuest, which enables searching all the CSD information fields, and the web implementation WebCSD software. Mercury is available for visualisation of crystal structures and crystal morphology including intra-and intermolecular interactions with graph-set notations of hydrogen bonds, and analysis of geometrical parameters. The CCDC gives even more options to the users developing sophisticated software such as GOLD, IsoStar and SuperStar, DASH, and extensive knowledge electronic libraries such as Mogul and Relibase. The CCDC released the new facility -Mercury's Solid Form module. Such demanding projects require a highly competent team of experts with a scientific approach based on the long tradition in crystallography, modelling and informatics. The Cambridge Structural Database and diversified software and searching engines are useful tools in research and teaching. The use of electronic media and computer graphics makes "data mining" very efficient and useful, but also aesthetically appealing due to the molecular architecture. One can expect even more advanced approaches using cloud computing and 'Big Data' management; merging data from related databases will enable to recognize hidden molecular and crystal properties and information that could bring new important knowledge. Since 1985, the CSD has been available to users in Croatia. The use of the CSD in Croatia is illustrated by a few examples per...

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Validating and Understanding Ring Conformations Using Small Molecule Crystallographic Data

Cited by 49 publications

References 44 publications

Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs

Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs

New active leads for tuberculosis booster drugs by structure-based drug discovery

Fiftieth Anniversary of the Cambridge Structural Database and Thirty Years of Its Use in Croatia

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