Abstract：
:Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013 , 22 , 101 - 113 ; Ahn, K. H. et al. Proteins 2013 , 81 , 1304 - 1317] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Scott CE,Ahn KH,Graf ST,Goddard WA 3rd,Kendall DA,Abrol Rdoi
10.1021/acs.jcim.5b00581subject
Has Abstractpub_date
2016-01-25 00:00:00pages
201-12issue
1eissn
1549-9596issn
1549-960Xjournal_volume
56pub_type
杂志文章abstract：:Activity cliffs are formed by structurally similar compounds having large potency differences. Coordinated activity cliffs evolve when compounds within groups of structural neighbors form multiple cliffs with different partners, giving rise to local networks of cliffs in a data set. Using particle swarm optimization, ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci3000503
更新日期：2012-04-23 00:00:00
abstract：:Flavonoids, the vastest class of natural polyphenols, are extensively investigated for their multiple benefits on human health. Due to their physicochemical or biological properties, many representatives are considered to exhibit low selectivity among various protein targets or to plague high-throughput screening (HTS...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci5002668
更新日期：2014-08-25 00:00:00
abstract：:Cytochrome P450 2D6 (CYP2D6) is used to develop an approach for predicting affinity and relevant binding conformation(s) for highly flexible binding sites. The approach combines the use of docking scores and compound properties as attributes in building a neural network (NN) model. It begins by identifying segments of...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci600267k
更新日期：2006-11-01 00:00:00
abstract：:We describe here our tool named PyPLIF HIPPOS, which was newly developed to analyze the docking results of AutoDock Vina and PLANTS. Its predecessor, PyPLIF (https://github.com/radifar/pyplif), is a molecular interaction fingerprinting tool for the docking results of PLANTS, exclusively. Unlike its predecessor, PyPLIF...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00305
更新日期：2020-08-24 00:00:00
abstract：:In the present contribution, we have developed a database, called the FAR-database, where the acronym FAR stands for Fused Aromatic Rings, which presents the results of nuclear independent chemical shifts calculations, NICS(0), NICS(1), NICS(0)ZZ, and NICS(1)ZZ, of 660 neutral benzenoid-PAHs and cyclopenta-fused PAHs....
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00909
更新日期：2020-02-24 00:00:00
abstract：:The recent article "Evaluation of pK(a) Estimation Methods on 211 Druglike Compounds" ( Manchester, J.; et al. J. Chem Inf. Model. 2010, 50, 565-571 ) reports poor results for the program Epik. Here, we highlight likely sources for the poor performance and describe work done to improve the performance. Running Epik in...
journal_title：Journal of chemical information and modeling
pub_type： 评论,杂志文章
doi：10.1021/ci100332m
更新日期：2011-01-24 00:00:00
abstract：:We develop the idea that the use of ad hoc molecular descriptors in QSAR/QSPR studies is not an optimal solution. Instead, we propose to optimize these descriptors for the specific properties under study. In the case of topological indices (TIs) we propose the use of the generalized topological indices (GTIs), which a...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci600448b
更新日期：2007-05-01 00:00:00
abstract：:A new structure classification scheme for biopolymers is introduced, which is solely based on main-chain dihedral angles. It is shown that by dividing a biopolymer into segments containing two central residues, a local classification can be performed. The method is referred to as DISICL, short for Dihedral-based Segme...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400541d
更新日期：2014-01-27 00:00:00
abstract：:Molecular docking can account for receptor flexibility by combining the docking score over multiple rigid receptor conformations, such as snapshots from a molecular dynamics simulation. Here, we evaluate a number of common snapshot selection strategies using a quality metric from stratified sampling, the efficiency of...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00314
更新日期：2018-09-24 00:00:00
abstract：:The SZMAP method computes binding free energies and the corresponding thermodynamic components for water molecules in the binding site of a protein structure [ SZMAP, 1.0.0 ; OpenEye Scientific Software Inc. : Santa Fe, NM, USA , 2011 ]. In this work, the ability of SZMAP to predict water structure and thermodynamic s...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci500746d
更新日期：2015-08-24 00:00:00
abstract：:The momentum gained by research on biologics has not been met yet with equal thrust on the informatics side. There is a noticeable lack of software for data management that empowers the bench scientists working on the development of biologic therapeutics. SARvision|Biologics is a tool to analyze data associated with b...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400333x
更新日期：2013-10-28 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：:Engineered nanomaterials (ENMs) are increasingly infiltrating our lives as a result of their applications across multiple fields. However, ENM formulations may result in the modulation of pathways and mechanisms of toxic action that endanger human health and the environment. Alternative testing methods such as in sili...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00223
更新日期：2017-09-25 00:00:00
abstract：:New hits against HIV-1 wild-type and Y181C drug-resistant reverse transcriptases were predicted taking into account the possibility of some of the known metabolism interactions. In silico hits against a set of antitargets (i.e., proteins or nucleic acids that are off-targets from the desired pharmaceutical target obje...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200203h
更新日期：2011-10-24 00:00:00
abstract：:The emergence of a large amount of pharmacological, genomic, and network knowledge data provides new challenges and opportunities for drug discovery and development. Identification of real small-molecule drug (SM)-miRNA associations is not only important in the development of effective drug repositioning but also cruc...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00244
更新日期：2020-08-24 00:00:00
abstract：:With the hope of discovering effective analgesics with fewer side effects, attention has recently shifted to allosteric modulators of the opioid receptors. In the past two years, the first chemotypes of positive or silent allosteric modulators (PAMs or SAMs, respectively) of μ- and δ-opioid receptor types have been re...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00388
更新日期：2015-09-28 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 consistent handling of molecules is probably the most basic and important requirement in the field of cheminformatics. Reliable results can only be obtained if the underlying calculations are independent of the specific way molecules are represented in the input data. However, ensuring consistency is a complex tas...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400724v
更新日期：2014-03-24 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：:Homology modeling is a reliable method of predicting the three-dimensional structures of proteins that lack NMR or X-ray crystallographic data. It employs the assumption that a structural resemblance exists between closely related proteins. Despite the availability of many crystal structures of possible templates, onl...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci500001f
更新日期：2014-06-23 00:00:00
abstract：:Saturated acyclic alkanes show steric strain if they are highly branched and, in extreme cases, fall apart rapidly at room temperature. Consequently, attempts to count the number of isomeric forms for a given molecular formula that neglect this physical consideration will inevitably overestimate the size of the availa...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci700246b
更新日期：2007-11-01 00:00:00
abstract：:The present study focuses on the determination of the biologically significant N-acetylneuraminic acid (NANA) drug binding interaction mechanism between bovine serum albumin (BSA) and human α-1 acid glycoprotein (HAG) using various optical spectroscopy and computational methods. The steady state fluorescence spectrosc...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00558
更新日期：2019-01-28 00:00:00
abstract：:We have performed a systematic study of the entropy term in the MM/GBSA (molecular mechanics combined with generalized Born and surface-area solvation) approach to calculate ligand-binding affinities. The entropies are calculated by a normal-mode analysis of harmonic frequencies from minimized snapshots of molecular d...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci3001919
更新日期：2012-08-27 00:00:00
abstract：:Methods that rapidly evaluate molecular complexity and synthetic feasibility are becoming increasingly important for in silico chemistry. We propose a new metric based on relative atomic electronegativities and bond parameters that evaluate both synthetic and molecular complexity (SMCM) starting from chemical structur...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0501387
更新日期：2005-09-01 00:00:00
abstract：:SMIfp (SMILES fingerprint) is defined here as a scalar fingerprint describing organic molecules by counting the occurrences of 34 different symbols in their SMILES strings, which creates a 34-dimensional chemical space. Ligand-based virtual screening using the city-block distance CBD(SMIfp) as similarity measure provi...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400206h
更新日期：2013-08-26 00:00:00
abstract：:With continually increased computer power, molecular mechanics force field-based approaches, such as the endpoint methods of molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA), have been routinely applied in both drug lead identification and opt...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00934
更新日期：2020-12-28 00:00:00
abstract：:The more that is known about human and other genome sequences and the correlation between gene expression and the course of a disease, the more evident it seems to be that DNA is chosen as a drug target instead of proteins which are built with the information encoded by DNA. According to this approach, small minor gro...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci600500v
更新日期：2007-07-01 00:00:00
abstract：:The early stages of drug discovery rely on hit-to-lead programs, where initial hits undergo partial optimization to improve binding affinities for their biological target. This is an expensive and time-consuming process, requiring multiple iterations of trial and error designs, an ideal scenario for applying computer ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00938
更新日期：2020-03-23 00:00:00
abstract：:Congeners are molecules based on the same carbon skeleton but are different by the number of substituents and/or a substitution pattern. Examples are 1-chloronaphthalene, 1,4-dichloronaphthalene, and 1,3,8-trichloronaphthalene. Various persistent organic pollutants (POPs) exist in the environment as families of congen...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci300289b
更新日期：2012-11-26 00:00:00
abstract：:Given the need for modern researchers to produce open, reproducible scientific output, the lack of standards and best practices for sharing data and workflows used to produce and analyze molecular dynamics (MD) simulations has become an important issue in the field. There are now multiple well-established packages to ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00665
更新日期：2019-10-28 00:00:00
