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Fragment-based identification of multi-target ligands by self-organizing map alignment

Janosch Achenbach, Franca-Maria Klingler, Steffen Hahn, Svenja Steinbrink, Mirjam Schroeder, Frank Loehr, Volker Doetsch, Dieter Steinhilber, Ewgenij Proschak
2012 Journal of Cheminformatics  
We present a new approach based on self-organizing maps [3, 6] (SOM) for the identification of multi-target fragments.  ...  Furthermore, these substructures are trained together with a fragment library on additional SOMs to find new multi-target fragments, validated by saturation transfer difference (STD)-NMR and biochemical  ...  Open access provides opportunities to our colleagues in other parts of the globe, by allowing anyone to view the content free of charge.  ... 
doi:10.1186/1758-2946-4-s1-p57 pmcid:PMC3341322 fatcat:sy4w5vt3bzhdnhiv7mynsljjvm

Experiences From Developing Software for Large X-Ray Crystallography-Driven Protein-Ligand Studies

Nicholas M. Pearce, Rachael Skyner, Tobias Krojer
2022 Frontiers in Molecular Biosciences  
Crystal structures of target proteins in complex with small-molecule ligands are of immense importance for structure-based drug design (SBDD) and their rapid turnover is a prerequisite for accelerated  ...  These developments have in turn spurred the development of several dedicated centers for crystal-based fragment screening which enable the preparation and collection of hundreds of single-crystal diffraction  ...  The large-scale availability of related crystallographic datasets from fragment screening experiments enabled the development of a data-driven multi-dataset ligand identification method: PanDDA (Pearce  ... 
doi:10.3389/fmolb.2022.861491 pmid:35480897 pmcid:PMC9035521 fatcat:l6fpnkmppbaxpdmiury2qr2fiy

QSAR and its Role in Target-Ligand Interaction

Dr. Anamika Singh
2013 The Open Bioinformatics Journal  
By QSAR models, the biological activity of a new or untested chemical can be inferred from the molecular structure of similar compounds whose activities have already been assessed.  ...  Structure and function of a molecule are related to each other and QSARs (Quantitative Structure-Activity relationships) are based on the criteria that the structure of a molecule must contain the features  ...  Self organizing molecular field analysis (SOMFA) is a novel 3D-QSAR methodology which has been developed by Robinson et al. [24] .  ... 
doi:10.2174/1875036201307010063 fatcat:hmsymvtbmrhktmqo4aeq2yuwaa

Two Decades of 4D-QSAR: A Dying Art or Staging a Comeback?

Andrzej Bak
2021 International Journal of Molecular Sciences  
MD-based simulations of the protein-ligand complexes.  ...  Typically, the postulated 'bioactive' 3D ligand conformation is constructed as a 'sophisticated guess' (unnecessarily geometry-optimized) mirroring the pharmacophore hypothesis—sometimes based on an erroneous  ...  Conflicts of Interest: The authors declare no conflict of interest.  ... 
doi:10.3390/ijms22105212 pmid:34069090 pmcid:PMC8156896 fatcat:rzktyhk6tzaa3ifiqhg6hbyjpa

Identification of Antifungal Targets Based on Computer Modeling

Elena Bencurova, Shishir Gupta, Edita Sarukhanyan, Thomas Dandekar
2018 Journal of Fungi  
We analyzed several of the best targets for application to structure-based drug design.  ...  Finally, we discuss general advantages and limitations in identification of unique fungal pathways and protein targets when applying bioinformatics tools.  ...  Funding: We thank DFG (TR124/B2; signalling, interactomics) and EU (European Union Infect-ERA program AspMetNet 031A408B, drug targeting of metabolism) for funding.  ... 
doi:10.3390/jof4030081 pmid:29973534 fatcat:sbwktk7mebbzli5tg5maxi6day

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Javier Vázquez, Manel López, Enric Gibert, Enric Herrero, F. Javier Luque
2020 Molecules  
A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets  ...  strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery  ...  (interaction fragments, IFs) and (ii) fragments generated by the random deletion of ligand atoms used as a control.  ... 
doi:10.3390/molecules25204723 pmid:33076254 fatcat:4gu5plnjwngr7dez7k3f5mnkre

Novel technologies for virtual screening

Thomas Lengauer, Christian Lemmen, Matthias Rarey, Marc Zimmermann
2004 Drug Discovery Today  
This method enables the grouping of compounds in a high-dimensional space by projecting them to 2D self-organizing maps (SOMs). 2D structural keys are used as descriptors.  ...  The alignment is derived by gradient-based optimization of a scoring function that assesses the overlap of the respective fields.  ... 
doi:10.1016/s1359-6446(04)02939-3 pmid:14761803 fatcat:kigd5ydnirbphig6cv3ciyp4xy

Mapping the Druggable Allosteric Space of G-Protein Coupled Receptors: a Fragment-Based Molecular Dynamics Approach

Anthony Ivetac, J. Andrew McCammon
2010 Chemical Biology and Drug Design  
Supercomputing Center, the Center for Theoretical Biological Physics and the National Biomedical Computational Resource for computational resources and the National Science Foundation, the National Institutes of  ...  Having identified a series of potential allosteric binding sites, this work will serve as a springboard for structure and fragment-based lead identification methods.  ...  Our results define a set of five key nonorthosteric regions that act as consensus binding sites for organic probes and which may represent targets for allosteric ligands.  ... 
doi:10.1111/j.1747-0285.2010.01012.x pmid:20626410 pmcid:PMC2918726 fatcat:xgupaxaqzrar5fgfvwriazfiru

TheXChemExplorergraphical workflow tool for routine or large-scale protein–ligand structure determination

Tobias Krojer, Romain Talon, Nicholas Pearce, Patrick Collins, Alice Douangamath, Jose Brandao-Neto, Alexandre Dias, Brian Marsden, Frank von Delft
2017 Acta Crystallographica Section D: Structural Biology  
XChemExplorer(XCE) is a data-management and workflow tool to support large-scale simultaneous analysis of protein–ligand complexes during structure-based ligand discovery (SBLD).  ...  Functionality to track progress and annotate structures is essential.XCEprovides an intuitive graphical user interface which guides the user from data processing, initial map calculation, ligand identification  ...  Acknowledgements The authors would like to thank David Damerell, Laura Diaz Saez, Joseph Newman, Dan Pinkas and Srikannathasan Velupillai for testing of the program and helpful feedback.  ... 
doi:10.1107/s2059798316020234 pmid:28291762 pmcid:PMC5349439 fatcat:e4x3osfj2vc6jl77kza3jlwha4

Genome-wide analysis of androgen receptor binding sites in prostate cancer cells

2015 Experimental and Therapeutic Medicine  
The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, mediates prostate cancer progression by functioning primarily through the ligand-activated transcription of target genes  ...  However, GO terms within the biological process domain that were only observed in the LNCaP-AI cells included the reproduction process, death, immune system process, multi-organism process, pigmentation  ...  Acknowledgements This study was supported by a grant from the National Natural Science Foundation of China (no. 81271917).  ... 
doi:10.3892/etm.2015.2406 pmid:26136980 pmcid:PMC4473645 fatcat:xavz6pynx5akthqh77hzw3g2vu

Computational Methodologies in the Exploration of Marine Natural Product Leads

Florbela Pereira, Joao Aires-de-Sousa
2018 Marine Drugs  
Structure-based (SB) and ligand-based (LB) chemoinformatics approaches have become essential tools for the virtual screening of NPs either in small datasets of isolated compounds or in large-scale databases  ...  ) properties, similarity searching, and pharmacophore identification.  ...  The SPiDER protocol performs a projection of query compounds, represented by pharmocophore topological descriptors, onto a self-organizing map (SOM) consisting of 120 receptive fields, which was previously  ... 
doi:10.3390/md16070236 pmid:30011882 pmcid:PMC6070892 fatcat:bqfrkq5acbce3eua6gk5sscy34

Advances in protein structure prediction and design

Brian Kuhlman, Philip Bradley
2019 Nature reviews. Molecular cell biology  
Methods for the prediction and design of protein structures have advanced dramatically in the past decade.  ...  In this Review, we describe current approaches for protein structure prediction and design and highlight a selection of the successful applications they have enabled.  ...  This work was supported by NIH grants R01GM117968 and R35GM131923 to B.K. and R01GM121487 and R01GM123378 to P.B.  ... 
doi:10.1038/s41580-019-0163-x pmid:31417196 pmcid:PMC7032036 fatcat:yw2q2q5dajh5bdsm5krjsbt4v4

In Silico Studies in Drug Research Against Neurodegenerative Diseases

Farahnaz Rezaei Makhouri, Jahan B. Ghasemi
2018 Current Neuropharmacology  
quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based  ...  Conclusion: Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of  ...  In addition, the capacity of the selected variables for discriminating the data was assessed by means of the unsupervised training of Kohonen Self-Organizing Maps (SOMs).  ... 
doi:10.2174/1570159x15666170823095628 pmid:28831921 pmcid:PMC6080098 fatcat:irfiwke6crgtphyqn2iv5wtl6y

Mapping of ligand-binding cavities in proteins

C. David Andersson, Brian Y. Chen, Anna Linusson
2009 Proteins: Structure, Function, and Bioinformatics  
Here, we present a novel approach to characterise and map the ligand-binding cavities of proteins without direct geometric comparison of structures, based on Principal Component Analysis of cavity properties  ...  mapping of "orphan structures", selection of protein structures for docking studies in structurebased design and identification of proteins for selectivity screens in drug design programs.  ...  Acknowledgments This work was funded by grants from the Swedish Research Council and financial support from AstraZeneca R&D Mölndal, Sweden.  ... 
doi:10.1002/prot.22655 pmid:20034113 pmcid:PMC2957484 fatcat:q7rjm37nefhlji3i7ljsisysdq

The 18th European Symposium on Quantitative Structure–Activity Relationships

Anna Tsantili-Kakoulidou, Dimitris K Agrafiotis
2011 Expert Opinion on Drug Discovery  
Wigley for the contribution to this work with the x-ray structure of the protein ligand to the GR1222222.  ...  Furthermore, the conducted docking studies elucidated the possible alternative binding mode of the ligands into the ATP binding cleft and assigned their physicochemical and structural features which promote  ...  lake sediments samples from Turawa Lake, Poland was analysed by application of self-organizing maps (SOMs).  ... 
doi:10.1517/17460441.2011.560604 pmid:22646021 fatcat:tb4bhvtnpzahxm4xba7iw4afuy
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