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Multiple conformational states in retrospective virtual screening – homology models vs. crystal structures: beta-2 adrenergic receptor case study

Stefan Mordalski, Jagna Witek, Sabina Smusz, Krzysztof Rataj, Andrzej J Bojarski
2015 Journal of Cheminformatics  
In this study, we compare the results of a retrospective screening of beta-2 adrenergic receptor ligands performed on both the ensemble of receptor conformations extracted from ten available crystal structures  ...  The use of homology models in such virtual screening application was proved to be superior in comparison to crystal structures.  ...  SM received funding for preparation of PhD thesis from Polish National Science Centre as part of PhD scholarship ETIUDA 2, decision DEC-2014/12/T/NZ2/00529  ... 
doi:10.1186/s13321-015-0062-x pmid:25949744 pmcid:PMC4420846 fatcat:rchlj7rpt5catlpbcveb2tbagu

Customizing G Protein-Coupled Receptor Models for Structure-Based Virtual Screening

Chris de Graaf, Didier Rognan
2009 Current pharmaceutical design  
In addition, the review will present a careful comparative analysis of current crystal structures and their implication on homology modeling.  ...  This review will focus on the construction, refinement, and validation of G Protein-coupled receptor models for the purpose of structure-based virtual screening.  ...  In one of the earliest reported retrospective VS studies [20] , the TM6 helix in bRho-based models of the adrenergic beta 2 (ADRB2), dopamine D2 (DRD2), and delta opioid (OPRD) receptors was rotated counter-clockwise  ... 
doi:10.2174/138161209789824786 pmid:20028320 fatcat:e2j3rcvtenbpne3xbnspjl526a

Structural Analysis of Chemokine Receptor–Ligand Interactions

Marta Arimont, Shan-Liang Sun, Rob Leurs, Martine Smit, Iwan J. P. de Esch, Chris de Graaf
2017 Journal of Medicinal Chemistry  
Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands  ...  of the structure of chemokine receptor−ligand complexes that have not been crystallized.  ...  Retrospective virtual screening experiments 24, 38, 208 have been used to validate and select optimal conformations of chemokine receptor homology models by assessing the ability of the model (and in  ... 
doi:10.1021/acs.jmedchem.6b01309 pmid:28165741 pmcid:PMC5483895 fatcat:tdjgkfdqafby3hwaa7w54wzkhm

A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design

A J Kooistra, S Kuhne, I J P de Esch, R Leurs, C de Graaf
2013 British Journal of Pharmacology  
crystallized aminergic GPCRs, and histamine receptors in particular.  ...  EXPERIMENTAL APPROACH In this study, we have combined ligand affinity data, receptor mutagenesis studies, and amino acid sequence analyses to high-resolution structural analyses of (hist)aminergic GPCR-ligand  ...  However, β2ARand H1R-based H4R homology models performed comparable in retrospective virtual screening studies (Istyastono, 2012) , and in recent prospective virtual screening runs Table 1 Binding affinities  ... 
doi:10.1111/bph.12248 pmid:23713847 pmcid:PMC3764853 fatcat:j4q5s2odz5gjpiw6idj5jwqpvq

Function-specific virtual screening for GPCR ligands using a combined scoring method

Albert J. Kooistra, Henry F. Vischer, Daniel McNaught-Flores, Rob Leurs, Iwan J. P. de Esch, Chris de Graaf
2016 Scientific Reports  
In another virtual screening study against the ß 2 -adrenoceptor (ß 2 R), Weiss et al. were able to identify 1 fragment-like and 5 lead-like ß 2 -adrenoceptor (ß 2 R) agonists by making use of both an  ...  Systematic retrospective virtual screening simulations allowed the definition of scoring cut-offs for the identification of H 1 R and ß 2 R ligands and the selection of an optimal ß-adrenoceptor crystal  ...  Retrospective virtual screening studies based on multiple different ß-adrenoceptor crystal structures allowed us to select an optimal combination of reference interaction fingerprint and protein conformation  ... 
doi:10.1038/srep28288 pmid:27339552 pmcid:PMC4919634 fatcat:a2wcdmbxjnal3lvvz3c63o3qum

Hierarchical virtual screening approaches in small molecule drug discovery

Ashutosh Kumar, Kam Y.J. Zhang
2015 Methods  
Several virtual screening studies are discussed to demonstrate the successful application of hierarchical virtual screening in small molecule drug discovery.  ...  Hierarchical combination of ligand and structure-based virtual screening approaches has received noteworthy success in numerous drug discovery campaigns.  ...  Homology model of 5-HT 1A R based on the active state of beta-2 adrenergic receptor was used for VS. Furthermore, de Graaf et al.  ... 
doi:10.1016/j.ymeth.2014.07.007 pmid:25072167 pmcid:PMC7129923 fatcat:t5mu2qmh5ncz3gwu3k2wnfr3t4

Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors

Damian Bartuzi, Agnieszka Kaczor, Katarzyna Targowska-Duda, Dariusz Matosiuk
2017 Molecules  
The growing number of studies on G protein-coupled receptors (GPCRs) family are a source of noticeable improvement in our understanding of the functioning of these proteins.  ...  One of the key steps in such studies is proper computational reconstruction of actual ligand-receptor or protein-protein interactions, a process called molecular docking.  ...  For GPCRs reported crystal structures are now applied in virtual screening to create homology models for close homologs.  ... 
doi:10.3390/molecules22020340 pmid:28241450 fatcat:xyytfxpfcvd43dyoefto4qr5pi

ALiBERO: Evolving a Team of Complementary Pocket Conformations Rather than a Single Leader

Manuel Rueda, Max Totrov, Ruben Abagyan
2012 Journal of Chemical Information and Modeling  
Docking and virtual screening (VS) reach maximum potential when the receptor displays the structural changes needed for accurate ligand binding.  ...  Unfortunately, these conformational changes are often poorly represented in experimental structures or homology models, debilitating their docking performance.  ...  beta-2 adrenergic receptor; PDB ID 2RH1; sequence identity with removed T4L fusion domain ∼30%).  ... 
doi:10.1021/ci3001088 pmid:22947092 pmcid:PMC3478405 fatcat:qecfg4ccszgobn62tfh3c5n47e

Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design

Shaherin Basith, Minghua Cui, Stephani J. Y. Macalino, Jongmi Park, Nina A. B. Clavio, Soosung Kang, Sun Choi
2018 Frontiers in Pharmacology  
Conformation guides molecular efficacy in docking screens of activated beta-2 adrenergic G protein coupled receptor. ACS Chem.  ...  Apart from the reported VS studies using crystal structures, there were also few reports using receptor homology models.  ... 
doi:10.3389/fphar.2018.00128 pmid:29593527 pmcid:PMC5854945 fatcat:drx2x7lo7jcehcto2ntknqsawe

The 18th European Symposium on Quantitative Structure–Activity Relationships

Anna Tsantili-Kakoulidou, Dimitris K Agrafiotis
2011 Expert Opinion on Drug Discovery  
We have recently reported on the CDK1 inhibitory activity of the pyrrolo [2,3-a]carbazole scaffold. 4 Molecular modeling and docking simulation studies explored the CDK1 binding mode of this core and  ...  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  ...  highthroughout screening (HTS) in vitro, or virtual screening (VS) in silico.  ... 
doi:10.1517/17460441.2011.560604 pmid:22646021 fatcat:tb4bhvtnpzahxm4xba7iw4afuy

Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies

Katarina Nikolic, Lazaros Mavridis, Teodora Djikic, Jelica Vucicevic, Danica Agbaba, Kemal Yelekci, John B. O. Mitchell
2016 Frontiers in Neuroscience  
The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure.  ...  Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs.  ...  4 | 4 Example case for the World Anti-Doping Agency data: the assignment of prohibited beta blockers to the Beta-2 adrenergic receptor family of ChEMBL (210).  ... 
doi:10.3389/fnins.2016.00265 pmid:27375423 pmcid:PMC4901078 fatcat:f7capvm2wnhmnmmlbj6bfui57u

A combined ligand-based and target-based drug design approach for G-protein coupled receptors: application to salvinorin A, a selective kappa opioid receptor agonist

Nidhi Singh, Gwénaël Chevé, David M. Ferguson, Christopher R. McCurdy
2006 Journal of Computer-Aided Molecular Design  
Therefore, we set out to develop a powerful virtual screening model to identify novel molecular scaffolds as potential leads for the human KOP (hKOP) receptor employing a combined approach.  ...  In addition, this model was in agreement with the mutation experiments carried out on KOP receptor.  ...  Introduction In recent years, virtual screening (VS) has emerged as a complementary method to high-throughput screening of large chemical databases in terms of time-efficiency and cost-effectiveness [  ... 
doi:10.1007/s10822-006-9067-x pmid:17009091 fatcat:aoeqek44cber3pp2uvcoo5evba

Improving virtual screening of G protein-coupled receptors via ligand-directed modeling

Thomas Coudrat, John Simms, Arthur Christopoulos, Denise Wootten, Patrick M. Sexton, Avner Schlessinger
2017 PLoS Computational Biology  
LDM-refined models showed improvement in VS performance over origin X-ray crystal structures in 21 out of 24 cases.  ...  In this study, the resulting models are evaluated both structurally, and in retrospective SBVS.  ...  Acknowledgments Computational studies were supported by Melbourne Bioinformatics at the University of Melbourne.  ... 
doi:10.1371/journal.pcbi.1005819 pmid:29131821 pmcid:PMC5708846 fatcat:ymjtsmav7ffd5gbnsbne4ggfmq

Pharmacophore-Based Similarity Scoring for DOCK

Lingling Jiang, Robert C. Rizzo
2014 Journal of Physical Chemistry B  
Retrospective analyses of virtual screenings to three clinical drug targets (EGFR, IGF-1R, and HIVgp41) using X-ray structures of known inhibitors as pharmacophore references are also reported, including  ...  In this study, we have encoded a three-dimensional pharmacophore matching similarity (FMS) scoring function into the structure-based design program DOCK.  ...  Finally, retrospective analyses of three virtual screens to targets of pharmaceutical interest (EGFR, IGF-1R, and HIVgp41) are shown in which FMSbased scoring (FMS and FMS+SGE) was used as a data-mining  ... 
doi:10.1021/jp506555w pmid:25229837 pmcid:PMC4306494 fatcat:knblawt4yreyxlarfq5m34q36i

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Outi M. H. Salo-Ahen, Ida Alanko, Rajendra Bhadane, Alexandre M. J. J. Bonvin, Rodrigo Vargas Honorato, Shakhawath Hossain, André H. Juffer, Aleksei Kabedev, Maija Lahtela-Kakkonen, Anders Støttrup Larsen, Eveline Lescrinier, Parthiban Marimuthu (+7 others)
2020 Processes  
recent studies as examples.  ...  Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple  ...  Even though recent crystal structures have demonstrated multiple conformational states of RAS, in all crystal structures of KRAS, the switch regions, when not disordered, are stabilized by crystal contacts  ... 
doi:10.3390/pr9010071 fatcat:x6pcyzoxevbvhncirfrkqiuppq
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