Generation of Molecular Shape Diverstiy. From Privileged Scaffolds to Diverted Total Synthesis

2012 ◽  
Vol 1 (1) ◽  
Author(s):  
Wei-Min Dai
Keyword(s):  
Total Synthesis ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Molecular Shape ◽  
Dimensional Structure ◽  
Diversity Oriented Synthesis ◽  
Biological Targets ◽  
Compound Libraries ◽  
Marine Macrolides ◽  
Potential Map

AbstractMolecular shape is a presentation of a molecule’s three-dimensional structure and its volume of space and surface electrostatic potential map collectively define the function, e. g. as a modulator or probe to biological targets. Molecular shape diversity for compound libraries with multiple scaffolds (rich skeletal diversity) is recognized as a prerequisite for discovering broad bioactivity. Established strategies and methodologies for diversity-oriented synthesis (DOS) are useful for generating molecular shape diversity by synthesizing natural product-like compounds. On the other hand, diverted total synthesis (DTS) offers natural products and analogues with a higher degree of structural diversity and complexity. Examples of DOS of privileged heterocycles and DTS of amphidinolide T marine macrolides from the author’s laboratories are illustrated.

Synthetic Strategies to Access Heteroatomic Spirocentres Embedded in Natural Products

Synthesis ◽  
2021 ◽  
Author(s):  
Michael P. Badart ◽  
Bill C. Hawkins
Keyword(s):  
Natural Products ◽  
Heterocyclic Compound ◽  
Chemical Space ◽  
Three Dimensional ◽  
Coupling Reactions ◽  
Conjugate Additions ◽  
Biological Targets ◽  
Compound Libraries ◽  
The Common ◽  
Significant Attention

AbstractThe spirocyclic motif is abundant in natural products and provides an ideal three-dimensional template to interact with biological targets. With significant attention historically expended on the synthesis of flat-heterocyclic compound libraries, methods to access the less-explored three-dimensional medicinal-chemical space will continue to increase in demand. Herein, we highlight by reaction class the common strategies used to construct the spirocyclic centres embedded in a series of well-studied natural products.1 Introduction2 Cycloadditions3 Palladium-Catalysed Coupling Reactions4 Conjugate Additions5 Imines, Aminals, and Hemiaminal Ethers6 Mannich-Type Reactions7 Oxidative Dearomatisation8 Alkylation9 Organometallic Additions10 Conclusions

Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

2013 ◽  
Vol 1 (1) ◽  
Author(s):  
Warren R.J.D. Galloway ◽  
David R. Spring
Keyword(s):  
Small Molecule ◽  
Structural Diversity ◽  
Library Size ◽  
Diversity Oriented Synthesis ◽  
Biological Targets ◽  
Small Molecule Screening ◽  
Chemistry Research ◽  
Large Numbers ◽  
Small Molecule Libraries ◽  
Scaffold Diversity

AbstractMedicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.

scholarly journals TransformerCPI: improving compound–protein interaction prediction by sequence-based deep learning with self-attention mechanism and label reversal experiments

2020 ◽  
Vol 36 (16) ◽  
pp. 4406-4414 ◽  
Author(s):  
Lifan Chen ◽  
Xiaoqin Tan ◽  
Dingyan Wang ◽  
Feisheng Zhong ◽  
Xiaohong Liu ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Three Dimensional ◽  
Prediction Performance ◽  
Dimensional Structure ◽  
Sequence Information ◽  
Biological Targets ◽  
Interaction Prediction ◽  
Protein Interaction Prediction ◽  
Improved Performance ◽  
Ligand Bias

Abstract Motivation Identifying compound–protein interaction (CPI) is a crucial task in drug discovery and chemogenomics studies, and proteins without three-dimensional structure account for a large part of potential biological targets, which requires developing methods using only protein sequence information to predict CPI. However, sequence-based CPI models may face some specific pitfalls, including using inappropriate datasets, hidden ligand bias and splitting datasets inappropriately, resulting in overestimation of their prediction performance. Results To address these issues, we here constructed new datasets specific for CPI prediction, proposed a novel transformer neural network named TransformerCPI, and introduced a more rigorous label reversal experiment to test whether a model learns true interaction features. TransformerCPI achieved much improved performance on the new experiments, and it can be deconvolved to highlight important interacting regions of protein sequences and compound atoms, which may contribute chemical biology studies with useful guidance for further ligand structural optimization. Availability and implementation https://github.com/lifanchen-simm/transformerCPI.

scholarly journals Structural diversity induced by ligand geometry: From two-dimensional to three-dimensional coordination polymers with pyridine

2020 ◽  
pp. 174751982096816
Author(s):  
Fang-Kuo Wang ◽  
Shi-Yao Yang ◽  
Hua-Ze Dong
Keyword(s):  
Coordination Polymers ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Dimensional Structure ◽  
Layer By Layer ◽  
Two Dimensional ◽  
Guest Molecules ◽  
X Ray ◽  
Benzenedicarboxylic Acid ◽  
Benzenetricarboxylic Acid

Two coordination polymers with two-dimensional and three-dimensional structures are, {[Zn3(bdc)3(py)2]·2NMP}n (1) (H2bdc = 1,4-benzenedicarboxylic acid) and [Zn2(NO3−)(btc)(nmp)2(py)]n (2) (H3btc = 1,3,5-benzenetricarboxylic acid), synthesized by hot-solution reactions of Zn(NO3)2·6H2O, pyridine (py) and two different ligands in N-methylpyrrolidone (NMP). {[Zn3(bdc)3(py)2]·2NMP}n exhibits two-dimensional networks with trizinc subunits [Zn3(COO)6py2] stacking with a layer-by-layer alignment, and there are strong π–π interactions involving py from adjacent layers. [Zn2(NO3−)(btc)(nmp)2(py)]n has a three-dimensional structure containing two independent zinc ions, tetrahedral ZnO4 and octahedral ZnNO5. Based on X-ray studies, the coordination polymers {[Zn3(bdc)3(py)2]·2NMP}n (1) have a porous structure with NMP guest molecules. In contrast, X-ray studies revealed that coordination polymer [Zn2(NO3−)(btc)(nmp)2(py)]n (2) had a larger void that was inhabited by coordinated py and NMP. In addition, the form of the two coordination polymers changed from two-dimensional to three-dimensional with transformation of the ligand geometry.

IN SEARCH OF THE PROTEIN NATIVE STATE WITH A PROBABILISTIC SAMPLING APPROACH

2011 ◽  
Vol 09 (03) ◽  
pp. 383-398 ◽  
Author(s):  
BRIAN OLSON ◽  
KEVIN MOLLOY ◽  
AMARDA SHEHU
Keyword(s):  
Structure Prediction ◽  
Computational Models ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Search Space ◽  
Conformational Space ◽  
Conformational Search ◽  
Dimensional Structure ◽  
Computational Techniques ◽  
Native State

The three-dimensional structure of a protein is a key determinant of its biological function. Given the cost and time required to acquire this structure through experimental means, computational models are necessary to complement wet-lab efforts. Many computational techniques exist for navigating the high-dimensional protein conformational search space, which is explored for low-energy conformations that comprise a protein's native states. This work proposes two strategies to enhance the sampling of conformations near the native state. An enhanced fragment library with greater structural diversity is used to expand the search space in the context of fragment-based assembly. To manage the increased complexity of the search space, only a representative subset of the sampled conformations is retained to further guide the search towards the native state. Our results make the case that these two strategies greatly enhance the sampling of the conformational space near the native state. A detailed comparative analysis shows that our approach performs as well as state-of-the-art ab initio structure prediction protocols.

scholarly journals IN SILICO STUDIES OF SOPHORAFLAVANONE G: QUANTUM CHARACTERIZATION AND ADMET

2020 ◽  
Vol 7 (11) ◽  
pp. 160-179 ◽  
Author(s):  
David Lopes Santiago De Oliveira ◽  
Emanuelle Machado Marinho ◽  
Francisco Nithael Melo Lucio ◽  
Marcia Machado Marinho ◽  
Francisco Rogênio Da Silva Mendes ◽  
...  
Keyword(s):  
Estrogen Receptor Alpha ◽  
Therapeutic Potential ◽  
Early Stage ◽  
Biological Activities ◽  
Three Dimensional ◽  
New Drugs ◽  
Dimensional Structure ◽  
Skin Permeability ◽  
Biological Targets ◽  
In Silico Studies

Currently, the search for new drugs with greater therapeutic potential and less side effects has been fostered by the advancement of the use of molecular modeling drugs, which in addition to supporting the full characterization of the molecule, allow simple algorithms to predict pharmacokinetic. In this context the present work aimed to perform the electronic / structural characterization, to evaluate the pharmacokinetic properties and to perform a virtual screening of the possible biological targets of Sophoraflavonone G, a promising flavonone, which presents several pharmacological properties. Sophoraflavanone G was geometrically optimized by semi-empirical quantum calculations, plot the MESP, identifying the nucleophilic sites. Using the boundary orbitals, it was possible to identify a greater tendency for electron donation in relation to Naringeni, with lower ionization potential, higher hardness and less softness. With respect to pharmacokinetics Sophoraflavonone G confirmed the safety of the compound for oral administration with good skin permeability, which allows applications in topical formulations. Presents indications for gastro intestinal absorption, as for possible interactions with biological targets, interaction with the estrogen receptor alpha, sodium / glucose co-transporter 2, beta-secretase 1, cyclooxygenase-1.The data obtained from an early stage for a comparative analysis between its analogues and fundamental for future studies of relationships between the three-dimensional structure of Sophoraflavanone G and its biological activities.

scholarly journals 3-D Imaging of Crystals at Atomic Resolution

1994 ◽  
Vol 332 ◽  
Author(s):  
M.A. O'keefe ◽  
K.H. Downing ◽  
H-R. Wenk ◽  
Hu Meisheng
Keyword(s):  
Mechanical Stability ◽  
Three Dimensional ◽  
Inorganic Materials ◽  
Three Dimensions ◽  
Dimensional Structure ◽  
Structure Factors ◽  
Potential Map ◽  
Structure Determinations ◽  
Unit Cells ◽  
High Resolution Images

ABSTRACTElectron crystallography has now been used to investigate the structures of inorganic materials in three dimensions. As a test of the method, amplitudes and phases of structure factors were obtained experimentally from high resolution images of staurolite taken in a number of different projections. From images in five orientations, a three-dimensional Coulomb potential map was constructed with a resolution of better than 1.4Å. The map clearly resolves all the cations (Al,Si,Fe) in the structure, and all of the oxygen atoms. This method promises great potential for structure determinations of small domains in heterogeneous crystals which are inaccessible to x-ray analysis. Three-dimensional structure determinations should be possible on small domains only approximately 10 unit cells wide, and may resolve site occupancies in addition to atom positions. Given a microscope stage with a suitable range of tilt and enough mechanical stability, the method could also be applied to small crystalline particles larger than about 50Å to 100Å. In addition, it may be possible to apply the method to derive the two-dimensional structure of periodic defects.

scholarly journals Capturing the complexity of topologically associating domains through multi-feature optimization

2021 ◽  
Author(s):  
Natalie Sauerwald ◽  
Carl Kingsford
Keyword(s):  
Binding Sites ◽  
Three Dimensional ◽  
Replication Timing ◽  
Biological Properties ◽  
Ctcf Binding ◽  
Dimensional Structure ◽  
Biological Targets ◽  
Topologically Associating Domains ◽  
Contact Frequency ◽  
Algorithmic Framework

AbstractThe three-dimensional structure of human chromosomes is tied to gene regulation and replication timing, but there is still a lack of consensus on the computational and biological definitions for chromosomal substructures such as topologically associating domains (TADs). TADs are described and identified by various computational properties leading to different TAD sets with varying compatibility with biological properties such as boundary occupancy of structural proteins. We unify many of these computational and biological targets into one algorithmic framework that jointly maximizes several computational TAD definitions and optimizes TAD selection for a quantifiable biological property. Using this framework, we explore the variability of TAD sets optimized for six different desirable properties of TAD sets: high occupancy of CTCF, RAD21, and H3K36me3 at boundaries, reproducibility between replicates, high intra- vs inter-TAD difference in contact frequencies, and many CTCF binding sites at boundaries. The compatibility of these biological targets varies by cell type, and our results suggest that these properties are better reflected as subpopulations or families of TADs rather than a singular TAD set fitting all TAD definitions and properties. We explore the properties that produce similar TAD sets (reproducibility and inter- vs intra-TAD difference, for example) and those that lead to very different TADs (such as CTCF binding sites and inter- vs intra-TAD contact frequency difference).

scholarly journals Time for a Plant Structural Economics Spectrum

2020 ◽  
Author(s):  
Hans Verbeeck ◽  
Marijn Bauters ◽  
Jackson Toby ◽  
Alexander Schenkin ◽  
Mathias Disney ◽  
...  
Keyword(s):  
Woody Plants ◽  
Laser Scanning ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Functional Trait ◽  
Structural Features ◽  
Dimensional Structure ◽  
Leaf Economics Spectrum ◽  
Tree Form ◽  
Structural Trait

<p>We argue that tree and crown structural diversity can and should be integrated in the whole-plant economics spectrum. Ecologists have found that certain functional trait combinations have been more viable than others during evolution, generating a trait trade-off continuum which can be summarized along a few axes of variation, such as the “worldwide leaf economics spectrum” and the “wood economics spectrum”. However, for woody plants the crown structural diversity should be included as well in the recently introduced “global spectrum of plant form and function”, which now merely focusses on plant height as structural factor. The recent revolution in terrestrial laser scanning (TLS) unlocks the possibility to describe the three dimensional structure of trees quantitatively with unprecedented detail. We demonstrate that based on TLS data, a multidimensional structural trait space can be constructed, which can be decomposed into a few descriptive axes or spectra. We conclude that the time has come to develop a “structural economics spectrum” for woody plants based on structural trait data across the globe. We make suggestions as to what structural features might lie on this spectrum and how these might help improve our understanding of tree form-function relationships.</p>

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