Open Babel: An open chemical toolbox O'Boyle, Noel M; Banck, Michael; James, Craig A ...
Journal of cheminformatics,
10/2011, Letnik:
3, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Background
A frequent problem in computational modeling is the interconversion of chemical structures between different formats. While standard interchange formats exist (for example, Chemical Markup ...Language) and
de facto
standards have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chemistry data, differences in the data stored by different formats (0D versus 3D, for example), and competition between software along with a lack of vendor-neutral formats.
Results
We discuss, for the first time, Open Babel, an open-source chemical toolbox that speaks the many languages of chemical data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chemical and molecular data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion.
Conclusions
Open Babel presents a solution to the proliferation of multiple chemical file formats. In addition, it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chemical data in areas such as organic chemistry, drug design, materials science, and computational chemistry. It is freely available under an open-source license from
http://openbabel.org
.
The concept of a single chemical entity with desirable activity at more than one biological target is an attractive one. Increasingly, multiple complex biochemical pathways are implicated in a ...variety of diseases including cancer. Successful treatment of these conditions often depends on pharmaceutical intervention at multiple pathways, with a combination of different drugs. Designed multiple ligands (DMLs) are drugs which act at multiple biomolecular targets. Numerous terms have been used to describe such ligands, including multiple-target directed ligands, heterodimers, promiscuous drugs and pan-agonists. However, although there are many reported examples of multiple-targeting anti-cancer agents, no review of these has been presented to date. A huge variety of biological signalling-pathways, proteins and enzymes are currently targeted and implicated in the pathogenesis of cancer. This review will provide an overview of reported designed multiple ligands for cancer and an exploration of the advantages and drawbacks of such compounds. The review also provides brief commentaries on the biological processes and proteins that are currently targeted in cancer therapy and the potential for dual or triple targeting of these with designed multiple ligands.
Structure–activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including ...trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl “A” ring and 4-phenyl “B” ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G2/M arrest and apoptosis. Compound 90b possessed a mean GI50 value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity, and was shown to interact at the colchicine-binding site on β-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesized, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.
A matched molecular series is the general form of a matched molecular pair and refers to a set of two or more molecules with the same scaffold but different R groups at the same position. We describe ...Matsy, a knowledge-based method that uses matched series to predict R groups likely to improve activity given an observed activity order for some R groups. We compare the Matsy predictions based on activity data from ChEMBLdb to the recommendations of the Topliss tree and carry out a large scale retrospective test to measure performance. We show that the basis for predictive success is preferred orders in matched series and that this preference is stronger for longer series. The Matsy algorithm allows medicinal chemists to integrate activity trends from diverse medicinal chemistry programs and apply them to problems of interest as a Topliss-like recommendation or as a hypothesis generator to aid compound design.
Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were ...synthesized: series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERβ. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.
Background
Many computational chemistry analyses require the generation of conformers, either on-the-fly, or in advance. We present Confab, an open source command-line application for the systematic ...generation of low-energy conformers according to a diversity criterion.
Results
Confab generates conformations using the 'torsion driving approach' which involves iterating systematically through a set of allowed torsion angles for each rotatable bond. Energy is assessed using the MMFF94 forcefield. Diversity is measured using the heavy-atom root-mean-square deviation (RMSD) relative to conformers already stored. We investigated the recovery of crystal structures for a dataset of 1000 ligands from the Protein Data Bank with fewer than 1 million conformations. Confab can recover 97% of the molecules to within 1.5 Å at a diversity level of 1.5 Å and an energy cutoff of 50 kcal/mol.
Conclusions
Confab is available from
http://confab.googlecode.com
.
We report the determination of the full stereostructure of (−)-ushikulide A (1), a spiroketal containing macrolide by total synthesis. Ushikulide A (1) was isolated from a culture broth of ...Streptomyces sp. IUK-102 and exhibits potent immunosuppressant activity (IC50 = 70 nM). To embark upon an ushikulide A synthesis, a tentative assignment was made based on analogy to cytovaricin (2), a related macrolide isolated from a culture of Streptomyces diastatochromogenes whose full structure was previously established via synthesis and X-ray crystallography. This report delineates studies on several key steps, namely a direct aldol reaction catalyzed by the dinuclear zinc ProPhenol complex, a metal catalyzed spiroketalization, as well as application of an unprecedented asymmetric alkynylation of a simple saturated aldehyde with methyl propiolate to prepare the nucleophilic partner for a Marshall−Tamaru propargylation. These studies culminated in the first total synthesis and stereochemical assignment of (−)-ushikulide A and significantly extended the scope of the above-mentioned methodologies.
The synthesis and antiproliferative activity of a new series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the ...usual ethylene bridge present in the natural combretastatin stilbene products. These novel compounds are also substituted at position 3 of the β-lactam ring with an aryl ring. A number of analogues showed potent nanomolar activity in human MCF-7 and MDA-MB-231 breast cancer cell lines, displayed in vitro inhibition of tubulin polymerization, and did not cause significant cytotoxicity in normal murine breast epithelial cells. 4-(4-Methoxyaryl)-substituted compound 32, 4-(3-hydroxy-4-methoxyaryl)-substituted compounds 35 and 41, and the 3-(4-aminoaryl)-substituted compounds 46 and 47 displayed the most potent antiproliferative activity of the series. β-Lactam 41 in particular showed subnanomolar activity in MCF-7 breast cancer cells (IC50 = 0.8 nM) together with significant in vitro inhibition of tubulin polymerization and has been selected for further biochemical assessment. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumor agents that target tubulin.
Lipids are an important constituent of skin and are known to be modified in many skin diseases including psoriasis and atopic dermatitis. The direct effects of common metallic contact allergens on ...the lipid composition of skin has never been investigated, to the best of our knowledge. We describe skin lipid profiles in the stratum corneum and viable epidermis of
ex vivo
human skin from a female donor upon exposure to three metal allergens (nickel, cobalt and chromium) visualised using time-of-flight secondary ion mass spectrometry (ToF-SIMS), which allows for simultaneous visualisation of both the allergen and skin components such as lipids. Multivariate analysis using partial least squares discriminant analysis (PLS-DA) indicated that the lipid profile of metal-treated skin was different to non-treated skin. Analysis of individual ions led to the discovery that cobalt and chromium induced increases in the content of diacylglycerols (DAG) in stratum corneum. Cobalt also induced increases in cholesterol in both the stratum corneum and viable epidermis, as well as monoacylglycerols (MAG) in the viable epidermis. Chromium caused an increase in DAG in viable epidermis in addition to the stratum corneum. In contrast, nickel decreased MAG and DAG levels in viable epidermis. Our results indicate that skin lipid content is likely to be altered upon topical exposure to metals. This discovery has potential implications for the molecular mechanisms by which contact allergens cause skin sensitization.
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