scholarly journals Ligand-Based Pharmacophore Modeling Using Novel 3D Pharmacophore Signatures

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3094 ◽  
Author(s):  
Alina Kutlushina ◽  
Aigul Khakimova ◽  
Timur Madzhidov ◽  
Pavel Polishchuk
Keyword(s):  
Open Source Software ◽  
Free Ligand ◽  
Software Tool ◽  
Pharmacophore Modeling ◽  
Template Molecule ◽  
Modeling Tools ◽  
Protein Targets ◽  
New Approach ◽  
3D Pharmacophore ◽  
Pharmacophore Models

Pharmacophore modeling is a widely used strategy for finding new hit molecules. Since not all protein targets have available 3D structures, ligand-based approaches are still useful. Currently, there are just a few free ligand-based pharmacophore modeling tools, and these have a lot of restrictions, e.g., using a template molecule for alignment. We developed a new approach to 3D pharmacophore representation and matching which does not require pharmacophore alignment. This representation can be used to quickly find identical pharmacophores in a given set. Based on this representation, a 3D pharmacophore ligand-based modeling approach to search for pharmacophores which preferably match active compounds and do not match inactive ones was developed. The approach searches for 3D pharmacophore models starting from 2D structures of available active and inactive compounds. The implemented approach was successfully applied for several retrospective studies. The results were compared to a 2D similarity search, demonstrating some of the advantages of the developed 3D pharmacophore models. Also, the generated 3D pharmacophore models were able to match the 3D poses of known ligands from their protein-ligand complexes, confirming the validity of the models. The developed approach is available as an open-source software tool: http://www.qsar4u.com/pages/pmapper.php and https://github.com/meddwl/psearch.

Virtual combinatorial chemistry and in silico screening: Efficient tools for lead structure discovery?

2004 ◽  
Vol 76 (5) ◽  
pp. 991-996 ◽  
Author(s):  
Thierry Langer ◽  
G. Wolber
Keyword(s):  
In Silico ◽  
Pharmacophore Model ◽  
Software Tool ◽  
Pharmacophore Modeling ◽  
In Silico Screening ◽  
Ionic Transfer ◽  
Automated Method ◽  
Small Molecule Ligands ◽  
Molecular Databases ◽  
Pharmacophore Models

In this article, an overview of the most common ligand-based in silico screening techniques is given together with an example on the recent successful application of combined use of pharmacophore modeling, database mining, and biological assays. Additionally, a new approach for structure-based high-throughput pharmacophore model generation is presented. The LigandScout program contains an automated method for creating pharmacophore models from experimentally determined structure data, e.g., publicly available from the Brookhaven Protein Databank (PDB). In a first step, known algorithms were implemented and improved to extract small-molecule ligands from the PDB including assignment of hybridization states and bond orders. Second, from the interactions of the interpreted ligands with relevant surrounding amino acids, pharmacophore models reflecting functional interactions like H-bonds or ionic transfer interactions were created. These models can be used for screening molecular databases for similar modes of actions on the one hand, or for screening one single compound for potential side-effects (reversed screening) on the other hand. The implementation was done using the ilib framework, which also formed the basis of the software tool CombiGen, a fragment-based virtual combinatorial library generation program enabling the user to obtain in silico compound collections with high drug-likeness.

scholarly journals Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor

2021 ◽  
Vol 16 (1) ◽  
pp. 303-310
Author(s):  
Lili Jiang ◽  
Zhongmin Zhang ◽  
Zhen Wang ◽  
Yong Liu
Keyword(s):  
Molecular Docking ◽  
Gastrointestinal Stromal Tumor ◽  
Pharmacophore Modeling ◽  
Stromal Tumor ◽  
Strong Hydrogen Bond ◽  
Ligand Complex ◽  
Hydrogen Bond Interaction ◽  
Mutant Proteins ◽  
Docking Simulations ◽  
Pharmacophore Models

Abstract Numerous inhibitors of tyrosine-protein kinase KIT, a receptor tyrosine kinase, have been explored as a viable therapy for the treatment of gastrointestinal stromal tumor (GIST). However, drug resistance due to acquired mutations in KIT makes these drugs almost useless. The present study was designed to screen the novel inhibitors against the activity of the KIT mutants through pharmacophore modeling and molecular docking. The best two pharmacophore models were established using the KIT mutants’ crystal complexes and were used to screen the new compounds with possible KIT inhibitory activity against both activation loop and ATP-binding mutants. As a result, two compounds were identified as potential candidates from the virtual screening, which satisfied the potential binding capabilities, molecular modeling characteristics, and predicted absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. Further molecular docking simulations showed that two compounds made strong hydrogen bond interaction with different KIT mutant proteins. Our results indicated that pharmacophore models based on the receptor–ligand complex had excellent ability to screen KIT inhibitors, and two compounds may have the potential to develop further as the future KIT inhibitors for GIST treatment.

Potenziale der Mehrmaschinenbedienung*/Potentials of multiple-machine operation

2016 ◽  
Vol 106 (04) ◽  
pp. 211-217
Author(s):  
M. Thurm ◽  
S. Horler ◽  
D. Oehme ◽  
A. Opitz ◽  
E. Prof. Müller
Keyword(s):  
Analytical Model ◽  
Production System ◽  
Analytical Approach ◽  
Software Tool ◽  
New Approach ◽  
Machine Operation ◽  
Resource Input

Die prozess- und kostenorientierte Auslegung der Mehrmaschinenbedienung soll mithilfe eines neuen analytischen Modellansatzes die Ressourcennutzung effizienter gestalten. Dabei steht die Integration von Mitarbeiterqualifikation und Maschinenpriorität im Fokus. Durch die später geplante Implementierung des neu entwickelten Ansatzes in das Softwaretool SmartPlanner der CAPPcore GmbH gelingt es, die Planung und Optimierung von Produktionssystemen zu verbessern.   A new approach for process and cost-related designing of multiplemachine operation is developed to optimize the resource input. Skills of employees and priority of machines have to be considered in the analytical model. The new analytical approach of multiple machine operation will be integrated in the software tool Smart Planner of the enterprise CAPPcore GmbH later on to improve the planning and optimization of the production system as a whole.

scholarly journals Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1959 ◽  
Author(s):  
Jérémie Mortier ◽  
Pratik Dhakal ◽  
Andrea Volkamer
Keyword(s):  
Protein Interactions ◽  
Pharmacophore Modeling ◽  
Macromolecular Structure ◽  
Target Structure ◽  
Protein Protein Interactions ◽  
Energy Functions ◽  
Chemical Structures ◽  
Molecular Interaction Fields ◽  
Protein Classes ◽  
Pharmacophore Models

Pharmacophore models are an accurate and minimal tridimensional abstraction of intermolecular interactions between chemical structures, usually derived from a group of molecules or from a ligand-target complex. Only a limited amount of solutions exists to model comprehensive pharmacophores using the information of a particular target structure without knowledge of any binding ligand. In this work, an automated and customable tool for truly target-focused (T²F) pharmacophore modeling is introduced. Key molecular interaction fields of a macromolecular structure are calculated using the AutoGRID energy functions. The most relevant points are selected by a newly developed filtering cascade and clustered to pharmacophore features with a density-based algorithm. Using five different protein classes, the ability of this method to identify essential pharmacophore features was compared to structure-based pharmacophores derived from ligand-target interactions. This method represents an extremely valuable instrument for drug design in a situation of scarce ligand information available, but also in the case of underexplored therapeutic targets, as well as to investigate protein allosteric pockets and protein-protein interactions.

scholarly journals An approach based on diffusion to study ligand-macromolecule interaction.

2002 ◽  
Vol 49 (3) ◽  
pp. 703-707 ◽  
Author(s):  
Mohammad R Housaindokht ◽  
Mahmood Bahrololoom ◽  
Shirin Tarighatpoor ◽  
Ali A Mossavi-Movahedi
Keyword(s):  
Methyl Orange ◽  
Diffusion Process ◽  
Binding Constant ◽  
Phosphate Buffer ◽  
Binding Capacity ◽  
Free Ligand ◽  
Hill Equation ◽  
New Approach ◽  
Binding Isotherm ◽  
The Hill

A new approach has been developed to study binding of a ligand to a macromolecule based on the diffusion process. In terms of the Fick's first law, the concentration of free ligand in the presence of a protein can be determined by the measurement of those ligands which are diffused out. This method is applied to the study of binding of methyl-orange to lysozyme in phosphate buffer of pH 6.2, at 30 degrees C. The binding isotherm was determined initially, followed by application of the Hill equation to the data obtained, then binding constant and binding capacity were estimated.

scholarly journals Cantera: an open source software tool for integrating complex thermo-chemistry into device-level simulations

2020 ◽  
Author(s):  
Richard West ◽  
Robert Kee ◽  
Kyle Niemeyer ◽  
Steven C. DeCaluwe ◽  
C. Goldsmith ◽  
...  
Keyword(s):  
Open Source ◽  
Open Source Software ◽  
Software Tool

scholarly journals An uncertainty-based protocol for the setup and measurement of soot/black carbon emissions from gas flares using sky-LOSA

2020 ◽  
Author(s):  
Bradley M. Conrad ◽  
Matthew R. Johnson
Keyword(s):  
Open Source ◽  
Black Carbon ◽  
Open Source Software ◽  
Carbon Emissions ◽  
Climate Models ◽  
Optical Measurement ◽  
Measurement Data ◽  
Software Tool ◽  
Measurement Protocol ◽  
Measurement Uncertainties

Abstract. Gas flaring is an important source of atmospheric soot/black carbon, especially in sensitive Arctic regions. However, emissions have traditionally been challenging to measure and remain poorly characterized, confounding international reporting requirements and adding uncertainty to climate models. The sky-LOSA optical measurement technique has emerged as a powerful means to quantify flare black carbon emissions in the field, but broader adoption has been hampered by the complexity of its deployment, where decisions during setup in the field can have profound, non-linear impacts on achievable measurement uncertainties. To address this challenge, this paper presents a prescriptive measurement protocol and associated open-source software tool that simplifies acquisition of sky-LOSA data in the field. Leveraging a comprehensive Monte Carlo-based General Uncertainty Analysis (GUA) to predict measurement uncertainties over the entire breadth of possible measurement conditions, general heuristics are identified to guide a sky-LOSA user toward optimal data collection. These are further extended in the open-source software utility, SetupSkyLOSA, which interprets the GUA results to provide detailed guidance for any specific combination of location, date/time, and flare, plume, and ambient conditions. Finally, a case study of a sky-LOSA measurement at an oil and gas facility in Mexico is used to demonstrate the utility of the software tool, where potentially small region(s) of optimal instrument setup are easily and quickly identified. It is hoped that this work will help increase the accessibility of the sky-LOSA technique and ultimately the availability of field measurement data for flare black carbon emissions.

scholarly journals A Tool for Local Thickness Determination and Grain Boundary Characterization by CTEM and HRTEM Techniques

2015 ◽  
Vol 21 (2) ◽  
pp. 422-435 ◽  
Author(s):  
Ákos K. Kiss ◽  
Edgar F. Rauch ◽  
Béla Pécz ◽  
János Szívós ◽  
János L. Lábár
Keyword(s):  
Grain Boundaries ◽  
Software Tool ◽  
Hexagonal Crystal ◽  
Electron Microscopic ◽  
Orientation Data ◽  
New Approach ◽  
Polycrystalline Thin Films ◽  
Transmission Electron ◽  
Transmission Electron Microscopic

AbstractA new approach for measurement of local thickness and characterization of grain boundaries is presented. The method is embodied in a software tool that helps to find and set sample orientations useful for high-resolution transmission electron microscopic (HRTEM) examination of grain boundaries in polycrystalline thin films. The novelty is thesimultaneoustreatment of the two neighboring grains and orienting both grains and the boundary planesimultaneously. The same metric matrix-based formalism is used for all crystal systems. Input into the software tool includes orientation data for the grains in question, which is determined automatically for a large number of grains by the commercial ASTAR program. Grain boundaries suitable for HRTEM examination are automatically identified by our software tool. Individual boundaries are selected manually for detailed HRTEM examination from the automatically identified set. Goniometer settings needed to observe the selected boundary in HRTEM are advised by the software. Operation is demonstrated on examples from cubic and hexagonal crystal systems.

Prospects of Open Source Software for Maximizing the User Expectations in Heterogeneous Network

2021 ◽  
pp. 257-271
Author(s):  
Pushpa Singh ◽  
Rajeev Agrawal
Keyword(s):  
Machine Learning ◽  
Open Source ◽  
Real Time ◽  
Open Source Software ◽  
Heterogeneous Networks ◽  
Heterogeneous Network ◽  
Research Work ◽  
Software Tool ◽  
Knn Classifier ◽  
User Expectations

This article focuses on the prospects of open source software and tools for maximizing the user expectations in heterogeneous networks. The open source software Python is used as a software tool in this research work for implementing machine learning technique for the categorization of the types of user in a heterogeneous network (HN). The KNN classifier available in Python defines the type of user category in real time to predict the available users in a particular category for maximizing profit for a business organization.

scholarly journals EVR: reconstruction of bacterial chromosome 3D structure models using error-vector resultant algorithm

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Kang-Jian Hua ◽  
Bin-Guang Ma
Keyword(s):  
Parallel Implementation ◽  
3D Structure ◽  
Software Tool ◽  
Structural Features ◽  
Bacterial Chromosome ◽  
Modeling Tools ◽  
Computing Power ◽  
Error Vector ◽  
Contact Frequency ◽  
Simple Error

Abstract Background More and more 3C/Hi-C experiments on prokaryotes have been published. However, most of the published modeling tools for chromosome 3D structures are targeting at eukaryotes. How to transform prokaryotic experimental chromosome interaction data into spatial structure models is an important task and in great need. Results We have developed a new reconstruction program for bacterial chromosome 3D structure models called EVR that exploits a simple Error-Vector Resultant (EVR) algorithm. This software tool is particularly optimized for the closed-loop structural features of prokaryotic chromosomes. The parallel implementation of the program can utilize the computing power of both multi-core CPUs and GPUs. Conclusions EVR can be used to reconstruct the bacterial 3D chromosome structure based on the contact frequency matrix derived from 3C/Hi-C experimental data quickly and precisely.

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