Abstract：
:G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, which is arguably the most important family of drug target. With the technology breakthroughs in X-ray crystallography and cryo-electron microscopy, more than 300 GPCR-ligand complex structures have been publicly reported since 2007, covering about 60 unique GPCRs. Such abundant structural information certainly will facilitate the structure-based drug design by targeting GPCRs. In this study, we have developed a fragment-based computational method for designing novel GPCR ligands. We first extracted the characteristic interaction patterns (CIPs) on the binding interfaces between GPCRs and their ligands. The CIPs were used as queries to search the chemical fragments derived from GPCR ligands, which were required to form similar interaction patterns with GPCR. Then, the selected chemical fragments were assembled into complete molecules by using the AutoT&T2 software. In this work, we chose β-adrenergic receptor (β-AR) and muscarinic acetylcholine receptor (mAChR) as the targets to validate this method. Based on the designs suggested by our method, samples of 63 compounds were purchased and tested in a cell-based functional assay. A total of 15 and 22 compounds were identified as active antagonists for β2-AR and mAChR M1, respectively. Molecular dynamics simulations and binding free energy analysis were performed to explore the key interactions (e.g., hydrogen bonds and π-π interactions) between those active compounds and their target GPCRs. In summary, our work presents a useful approach to the de novo design of GPCR ligands based on the relevant 3D structural information.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Li Y,Sun Y,Song Y,Dai D,Zhao Z,Zhang Q,Zhong W,Hu LA,Ma Y,Li X,Wang Rdoi
10.1021/acs.jcim.9b00699subject
Has Abstractpub_date
2020-09-28 00:00:00pages
4339-4349issue
9eissn
1549-9596issn
1549-960Xjournal_volume
60pub_type
杂志文章abstract：:Umami or the taste of monosodium glutamate represents one of the major attractive taste modalities in humans. Therefore, knowledge about biophysical and biochemical properties of the umami taste is important for both scientific research and the food industry. Experimental approaches for predicting umami peptides are l...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00707
更新日期：2020-12-28 00:00:00
abstract：:In this study, we aimed to develop a new ligand-based virtual screening approach using an effective shape-overlapping procedure and a more robust scoring function (denoted by the HWZ score for convenience). The HWZ score-based virtual screening approach was tested against the compounds for 40 protein targets available...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200617d
更新日期：2012-04-23 00:00:00
abstract：:The failure of default scoring functions to ensure virtual screening enrichment is a persistent problem for the molecular docking algorithms used in structure-based drug discovery. To remedy this problem, elaborate rescoring and postprocessing schemes have been developed with a varying degree of success, specificity, ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00383
更新日期：2019-08-26 00:00:00
abstract：:A model for prediction of percent intestinal absorption (%Abs) of neutral molecules was developed based upon surface charges of the molecule calculated by density functional theory (DFT). The surface charges are decomposed into sigma moments which are correlated to a partition coefficient representing transfer of the ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci049653f
更新日期：2005-09-01 00:00:00
abstract：:The modeling of nonlinear descriptor-target relationships is a topic of considerable interest in drug discovery. We, herein, continue reporting the use of the self-organizing map-a nonlinear, topology-preserving pattern recognition technique that exhibits considerable promise in modeling and decoding these relationshi...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0500841
更新日期：2006-01-01 00:00:00
abstract：:Naturally occurring anticancer compounds represent about half of the chemotherapeutic drugs which have been put in the market against cancer until date. Computer-based or in silico virtual screening methods are often used in lead/hit discovery protocols. In this study, the "drug-likeness" of ~400 compounds from Africa...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci5003697
更新日期：2014-09-22 00:00:00
abstract：:Peptide libraries allow researchers to quickly find hundreds of peptide sequences with a desired property. Currently, the large amount of data generated from peptide libraries is analyzed by hand, where researchers search for repeating patterns in the peptide sequences. Such patterns are called motifs. In this work, w...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci300484q
更新日期：2013-02-25 00:00:00
abstract：:We present a theoretical study on the performance of ensemble docking methodologies considering multiple protein structures. We perform a theoretical analysis of pose prediction experiments which is completely unbiased, as we make no assumptions about specific scoring functions, search paradigms, protein structures, o...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci2002796
更新日期：2011-11-28 00:00:00
abstract：:Our main objective was to compile a data set of high-quality protein-fragment complexes and make it publicly available. Once assembled, the data set was challenged using docking procedures to address the following questions: (i) Can molecular docking correctly reproduce the experimentally solved structures? (ii) How t...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci2003363
更新日期：2011-11-28 00:00:00
abstract：:A phenotypic screen (PS) is used to identify compounds causing a desired phenotype in a complex biological system where mechanisms and targets are largely unknown. Deconvoluting the mechanism of action of actives and identification of relevant targets and pathways remains a formidable challenge. Current methods fail t...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400245c
更新日期：2014-02-24 00:00:00
abstract：:Inhibitors of histone deacetylases (HDACIs) have emerged as a new class of drugs for the treatment of human cancers and other diseases because of their effects on cell growth, differentiation, and apoptosis. In this study we have developed several quantitative structure-activity relationship (QSAR) models for 59 chemi...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci800366f
更新日期：2009-02-01 00:00:00
abstract：:We used synthetic peloruside A for the commercial preparation of [³H]peloruside A. The radiolabeled compound bound to preformed tubulin polymer in amounts stoichiometric with the polymer's tubulin content, with an apparent K(d) value of 0.35 μM. A less active peloruside A analogue, (11-R)-peloruside A and laulimalide ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci1002894
更新日期：2010-11-22 00:00:00
abstract：:Support vector regression (SVR) is a premier approach for the prediction of compound potency. Given the conceptual link between support vector machine (SVM) and SVR modeling, SVR is capable of accounting for continuous and discontinuous structure-activity relationships (SARs) in potency prediction, which further exten...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00584
更新日期：2019-03-25 00:00:00
abstract：:A data set of 130 diverse compounds containing both central nervous system (CNS) and non-CNS drugs was used to generate a renal clearance model using a classical Volsurf approach. Percentage renal clearance data was used as a biological input. The score plots obtained from principal component analysis and partial leas...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0503309
更新日期：2006-05-01 00:00:00
abstract：:The molecular structure of four dimeric units (D-E, E-F, F-G, and G-H) of the DEFGH structural unit of heparin, their anionic forms, and their sodium salts have been studied using the B3LYP/6-31+G(d) method. The optimized geometries indicate that the most stable structure of these dimeric units in neutral state is sta...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci060060+
更新日期：2006-07-01 00:00:00
abstract：:The effects of paclitaxel (PTX) loading fraction and spatial PTX arrangement on poly(γ-glutamyl-glutamate) paclitaxel (PGG-PTX) aggregation were explored using coarse-grained molecular dynamics. Results show that the PTX loading fraction does not significantly impact aggregation, and the spatial PTX arrangement only a...
journal_title：Journal of chemical information and modeling
pub_type： 信件
doi：10.1021/ci200214m
更新日期：2011-12-27 00:00:00
abstract：:Class II fructose-1,6-bisphosphate aldolases (FBA-II) are attractive new targets for the discovery of drugs to combat invasive fungal infection, because they are absent in animals and higher plants. Although several FBA-II inhibitors have been reported, none of these inhibitors exhibit antifungal effect so far. In thi...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.6b00763
更新日期：2017-06-26 00:00:00
abstract：:An essential feature of all practical de novo molecule generating programs is the ability to focus the potential combinatorial explosion of grown molecules on a desired chemical space. It is a daunting task to balance the generation of new molecules with limitations on growth that produce desired features such as stab...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci9000458
更新日期：2009-07-01 00:00:00
abstract：:The emergence of multidrug-resistant Staphylococcus aureus (S. aureus) makes the treatment of infectious diseases in hospitals more difficult and increases the mortality of the patients. In this study, we attempted to identify novel potent antibiotic candidate compounds against S. aureus dihydrofolate reductase (saDHF...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400686d
更新日期：2014-04-28 00:00:00
abstract：:The roles of chemical compounds in biological systems are now systematically analyzed by high-throughput experimental technologies. To automate the processing and interpretation of large-scale data it is necessary to develop bioinformatics methods to extract information from the chemical structures of these small mole...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci700006f
更新日期：2007-07-01 00:00:00
abstract：:Membrane transporters play a crucial role in determining fate of administered drugs in a biological system. Early identification of plausible transporters for a drug molecule can provide insights into its therapeutic, pharmacokinetic, and toxicological profiles. In the present study, predictive models for classifying ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.6b00508
更新日期：2017-03-27 00:00:00
abstract：:Pharmacophore search is a key component of many drug discovery efforts. Pharmer is a new computational approach to pharmacophore search that scales with the breadth and complexity of the query, not the size of the compound library being screened. Two novel methods for organizing pharmacophore data, the Pharmer KDB-tre...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200097m
更新日期：2011-06-27 00:00:00
abstract：:Derivation of structure-kinetics relationships can help rational design and development of new small-molecule drug candidates with desired residence times. Efforts are now being directed toward the development of efficient computational methods. Currently, there is a lack of solid, high-throughput binding kinetics pre...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00450
更新日期：2020-12-28 00:00:00
abstract：:Scoring the activity of compounds in phenotypic high-throughput assays presents a unique challenge because of the limited resolution and inherent measurement error of these assays. Techniques that leverage the structural similarity of compounds within an assay can be used to improve the hit-recovery rate from screenin...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci050087d
更新日期：2005-11-01 00:00:00
abstract：:Traditional herbal medicine has been an inseparable part of the traditional medical science in many countries throughout history. Nowadays, the popularity of using herbal medicines in daily life, as well as clinical practices, has gradually expanded to numerous Western countries with positive impacts and acceptance. T...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00826
更新日期：2020-03-23 00:00:00
abstract：:Cytochrome P450 3A4 metabolizes nearly 50% of the drugs currently in clinical use with a broad range of substrate specificity. Early prediction of metabolites of xenobiotic compounds is crucial for cost efficient drug discovery and development. We developed a new combined model, MLite, for the prediction of regioselec...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci7003576
更新日期：2008-03-01 00:00:00
abstract：:Generalization of an earlier algorithm has led to the development of new local structural alignment algorithms for prediction of protein-protein binding sites. The algorithms use maximum cliques on protein graphs to define structurally similar protein regions. The search for structural neighbors in the new algorithms ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci100265x
更新日期：2010-10-25 00:00:00
abstract：:Encapsulation of peptide and protein-based drugs in polymeric nanoparticles is one of the fundamental fields in controlled-release drug delivery systems. The molecular mechanisms of absorption of peptides to the polymeric nanoparticles are still unknown, and there is no precise molecular data on the encapsulation proc...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00641
更新日期：2019-01-28 00:00:00
abstract：:The programs Phase and Catalyst HypoGen are compared for their performance in determining three-dimensional quantitative structure-activity relationships. Eight sets of compounds with measured activity were collected from the public literature and partitioned into suitable training and test sets by an automated proced...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci7000082
更新日期：2007-05-01 00:00:00
abstract：:Databases of small, potentially bioactive molecules are ubiquitous across the industry and academia. Designed such that each unique compound should appear only once, the multiplicity of ways in which many compounds can be represented means that these databases require methods for standardizing the representation of ch...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00232
更新日期：2020-08-24 00:00:00
