Abstract：
:The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore. As the 3D structure of human Nav1.2 is not available, we first assembled 3D models of the target, in closed and open conformations. After the virtual screening, the resulting candidates were submitted to a second virtual filter, to find compounds with better chances of being effective for the treatment of P-glycoprotein (P-gp) mediated resistant epilepsy. Again, we built a model of the 3D structure of human P-gp, and we validated the docking methodology selected to propose the best candidates, which were experimentally tested on Nav1.2 channels by patch clamp techniques and in vivo by the maximal electroshock seizure (MES) test. Patch clamp studies allowed us to corroborate that our candidates, drugs used for the treatment of other pathologies like Ciprofloxacin, Losartan, and Valsartan, exhibit inhibitory effects on Nav1.2 channel activity. Additionally, a compound synthesized in our lab, N, N'-diphenethylsulfamide, interacts with the target and also triggers significant Na1.2 channel inhibitory action. Finally, in vivo studies confirmed the anticonvulsant action of Valsartan, Ciprofloxacin, and N, N'-diphenethylsulfamide.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Palestro PH,Enrique N,Goicoechea S,Villalba ML,Sabatier LL,Martin P,Milesi V,Bruno Blanch LE,Gavernet Ldoi
10.1021/acs.jcim.7b00721subject
Has Abstractpub_date
2018-07-23 00:00:00pages
1331-1342issue
7eissn
1549-9596issn
1549-960Xjournal_volume
58pub_type
杂志文章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：:The Torsion Library contains hundreds of rules for small molecule conformations which have been derived from the Cambridge Structural Database (CSD) and are curated by molecular design experts. The torsion rules are encoded as SMARTS patterns and categorize rotatable bonds via a traffic light coloring scheme. We have ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00522
更新日期：2016-01-25 00:00:00
abstract：:Various cages are constructed by using three types of caps: f-cap (derived from spherical fullerenes by deleting zones of various size), kf-cap (obtainable by cutting off the polar ring, of size k), and t-cap ("tubercule"-cap). Building ways are presented, some of them being possible isomerization routes in the real c...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci049738g
更新日期：2005-03-01 00:00:00
abstract：:Solubility parameter models are widely used to select suitable solvents/nonsolvents for polymers in a variety of processing and engineering applications. In this study, we focus on two well-established models, namely, the Hildebrand and Hansen solubility parameter models. Both models are built on the basis of the noti...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00656
更新日期：2019-10-28 00:00:00
abstract：:Theoretical calculation of equilibrium dissociation constants is a very computationally demanding and time-consuming process since it requires an extremely accurate computation of the solvation free energy changes for each of the species involved. By correlating the minimum surface electrostatic potential (VS,min) on ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b01173
更新日期：2020-03-23 00:00:00
abstract：:Resonance structures of polycyclic aromatic hydrocarbons can be associated with numerical formulas by assigning pi-electrons of C=C double bonds to individual benzenoid rings. Each C=C double bond in a resonance structure assigns two pi-electrons to a ring in a fused-benzenoid system if it is not shared by adjacent ri...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci050196s
更新日期：2006-01-01 00:00:00
abstract：:Blockade of human ether-à-go-go related gene (hERG) channel prolongs the duration of the cardiac action potential and is a common reason for drug failure in preclinical safety trials. Therefore, it is of great importance to develop robust in silico tools to predict potential hERG blockers in the early stages of drug d...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200271d
更新日期：2011-11-28 00:00:00
abstract：:Computer-aided drug design methods such as docking, pharmacophore searching, 3D database searching, and the creation of 3D-QSAR models need conformational ensembles to handle the flexibility of small molecules. Here, we present Conformator, an accurate and effective knowledge-based algorithm for generating conformer e...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00704
更新日期：2019-02-25 00:00:00
abstract：:Artificial intelligence and multiobjective optimization represent promising solutions to bridge chemical and biological landscapes by addressing the automated de novo design of compounds as a result of a humanlike creative process. In the present study, we conceived a novel pair-based multiobjective approach implement...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00517
更新日期：2020-10-26 00:00:00
abstract：:Representative molecules from 10 classes of prohibited substances were taken from the World Anti-Doping Agency (WADA) list, augmented by molecules from corresponding activity classes found in the MDDR database. Together with some explicitly allowed compounds, these formed a set of 5245 molecules. Five types of fingerp...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0601160
更新日期：2006-11-01 00:00:00
abstract：:In this work, we present molecular modeling studies carried out using six DNA sequences and six azinomycin analogues, including the naturally occurring compound azinomycin B, selected on the basis of known cell cytotoxicity and structural analogies (epoxide and aziridine alkylating moieties). Among several computation...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0496595
更新日期：2005-05-01 00:00:00
abstract：:LEAFY (LFY) is a plant-specific transcription factor, with a variety of roles in different species. LFY contains a conserved DNA-binding domain (DBD) that determines its DNA-binding specificity. Recently, the structures of the dimeric LFY-DBD bound to different DNA motifs were successively solved by X-ray crystallogra...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci500705j
更新日期：2015-04-27 00:00:00
abstract：:Metal-ligand (M-L) bond lengths for a range of ligands (carboxylates, chlorides, pyridines, water, tertiary phosphines, and alkenes) and a variety of metals have been retrieved from the Cambridge Structural Database, CSD. Analysis of the factors which affect M-L bond lengths (for example, ligand coordination mode, oxi...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0500785
更新日期：2005-11-01 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 membrane permeability of cyclic peptides and peptidomimetics, which are generally larger and more complex than typical drug molecules, is likely strongly influenced by the conformational behavior of these compounds in polar and apolar environments. The size and complexity of peptides often limit their bioavailabil...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.6b00251
更新日期：2016-08-22 00:00:00
abstract：:Telomere maintenance is a universal cancer hallmark, and small molecules that disrupt telomere maintenance generally have anticancer properties. Since the vast majority of cancer cells utilize telomerase activity for telomere maintenance, the enzyme has been considered as an anticancer drug target. Recently, rational ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00336
更新日期：2015-12-28 00:00:00
abstract：:We describe a general methodology for designing an empirical scoring function and provide smina, a version of AutoDock Vina specially optimized to support high-throughput scoring and user-specified custom scoring functions. Using our general method, the unique capabilities of smina, a set of default interaction terms ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci300604z
更新日期：2013-08-26 00:00:00
abstract：:The possibility of improving the predictive ability of comparative molecular field analysis (CoMFA) by settings optimization has been evaluated to show that CoMFA predictive ability can be improved. Ten different CoMFA settings are evaluated, producing a total of 6120 models. This method has been applied to nine diffe...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci049612j
更新日期：2006-01-01 00:00:00
abstract：:Dynamical properties of proteins play an essential role in their function exertion. The elastic network model (ENM) is an effective and efficient tool in characterizing the intrinsic dynamical properties encoded in biomacromolecule structures. The Gaussian network model (GNM) and anisotropic network model (ANM) are th...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c01178
更新日期：2021-01-26 00:00:00
abstract：:The human cytochrome P450 1A2 is an important drug metabolizing and procarcinogen activating enzyme. An experimental study found that a peripheral mutation, F186L, at ∼26 Å away from the enzyme's active site, caused a significant reduction in the enzymatic activity of 1A2 deethylation reactions. In this paper, we expl...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200112b
更新日期：2011-06-27 00:00:00
abstract：:Molecular channel exploration perseveres to be the prominent solution for eliciting structure and accessibility of active site and other internal spaces of macromolecules. The volume and silhouette characterization of these channels provides answers for the issues of substrate access and ligand swapping between the ob...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200584f
更新日期：2012-02-27 00:00:00
abstract：:Binding hot spots are regions of proteins that, due to their potentially high contribution to the binding free energy, have high propensity to bind small molecules. We present benchmark sets for testing computational methods for the identification of binding hot spots with emphasis on fragment-based ligand discovery. ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00877
更新日期：2020-12-28 00:00:00
abstract：:Membrane fusion, a key step in the early stages of virus propagation, allows the release of the viral genome in the host cell cytoplasm. The process is initiated by fusion peptides that are small, hydrophobic components of viral membrane-embedded glycoproteins and are typically conserved within virus families. Here, w...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c01231
更新日期：2021-01-25 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：: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：:We report here on long-time all-atomistic molecular dynamics simulations of functional supramolecular nanotubes composed by the self-assembly of peptide-drug amphiphiles (DAs). These DAs have been shown to possess an inherently high drug loading of the hydrophobic anticancer drug camptothecin. We probe the self-assemb...
journal_title：Journal of chemical information and modeling
pub_type： 信件
doi：10.1021/acs.jcim.8b00193
更新日期：2018-06-25 00:00:00
abstract：:Previously, stereoselective hydroxylation of α-ionone by Cytochrome P450 BM3 mutants M01 A82W and M11 L437N was observed. While both mutants hydroxylate α-ionone in a regioselective manner at the C3 position, M01 A82W catalyzes formation of trans-3-OH-α-ionone products whereas M11 L437N exhibits opposite stereoselecti...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci300243n
更新日期：2012-08-27 00:00:00
abstract：:Dual and triple activity-difference (DAD/TAD) maps are tools for the systematic characterization of structure-activity relationships (SAR) of compound data sets screened against two or three targets. DAD and TAD maps are two- and three- dimensional representations of the pairwise activity differences of compound data ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200281v
更新日期：2011-09-26 00:00:00
abstract：:Taking into account dynamical behavior and/or structural inaccuracies of receptor-ligand systems becomes increasingly important in structure-based drug design. Here, we describe the development of consensus Adaptation of Fields for Molecular Comparison (AFMoC) (abbreviated as AFMoCcon) models that account for multiple...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci7002472
更新日期：2007-11-01 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
