Abstract：
:Overexpression of Bcl-2 and Bcl-xL proteins, both inhibitors of apoptosis or programmed cell death, is related to the generation and development of several types of cancer as well as to an elevated resistance to chemotherapeutic treatments. Given that synthetic peptide fragments of the BH3 domain are capable to bind to both proteins and induce apoptosis in cell-free systems and HeLa cells, small molecule non-peptide mimics of these peptides can be considered as a new therapeutic strategy for the treatment of diseases associated to a deficient apoptosis or resistant to the treatments with chemotherapeutic drugs. This strategy is supported by experimental evidences about the death of transformed cells and sensibilization of tumoral cells by the inhibition of the antiapoptotic proteins Bcl-2 and Bcl-xL. In the current work, these proteins complexed with X(16BH3), where X designates the proapoptotic proteins Bak, Bax, Bid and Hrk, have been modeled in order to establish a pharmacophoric hypothesis that must be present in any ligand capable of binding with the antiapoptotic proteins Bcl-2 and Bcl-xL. The pharmacophore is also used to explain the structural features of a set of new small molecule inhibitors of these antiapoptotic proteins.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Pinto M,Perez JJ,Rubio-Martinez Jdoi
10.1023/b:jcam.0000022559.72848.1csubject
Has Abstractpub_date
2004-01-01 00:00:00pages
13-22issue
1eissn
0920-654Xissn
1573-4951journal_volume
18pub_type
杂志文章abstract：:Thirty-six compounds, representing six different structural classes of insecticides which are known to act at the gamma-aminobutyric acid receptor/chloride ionophore, have been superimposed by methods which maximise the commonality of steric and electrostatic fields. Maximal steric and electrostatic alignment was deri...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00141574
更新日期：1993-02-01 00:00:00
abstract：:Atomic-resolution structures of the transmembrane 7-alpha-helical domains of 26 G-protein-coupled receptors (GPCRs) (including opsins, cationic amine, melatonin, purine, chemokine, opioid, and glycoprotein hormone receptors and two related proteins, retinochrome and Duffy erythrocyte antigen) were calculated by distan...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章,评审
doi：10.1023/a:1008050821744
更新日期：1999-07-01 00:00:00
abstract：:The Multiple Copy Simultaneous Search methodology has been used to construct functionality maps for an extended region of human thrombin, including the active site. This method allows the determination of energetically favorable positions and orientations for functional groups defined by the user on the three-dimensio...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00124460
更新日期：1996-02-01 00:00:00
abstract：:A combined strategy based on the development of pharmacophore hypotheses and NMR approaches is reported for the identification of novel inhibitors of heparanase, a key enzyme involved in tumor metastasis through the remodeling of the subepithelial and subendothelial basement membranes, resulting in the dissemination o...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-009-9269-0
更新日期：2009-08-01 00:00:00
abstract：:Modelling studies have been carried out on the phosphodiesterase (PDE) substrates, adenosine- and guanosine-3'5'-cyclic monophosphates, and on a number of non-specific and type III-specific phosphodiesterase inhibitors. These studies have assisted the understanding of PDE substrate differentiation and the design of po...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF01676955
更新日期：1987-07-01 00:00:00
abstract：:Starting from the X-ray structure of a class I major histocompatibility complex (MHC)-encoded protein (HLA-B*2705), a naturally presented self-nonapeptide and two synthetic analogues were simulated in the binding groove of two human leukocyte antigen (HLA) alleles (B*2703 and B*2705) differing in a single amino acid r...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1007963901092
更新日期：1997-09-01 00:00:00
abstract：:The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule i...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-019-00211-1
更新日期：2019-07-01 00:00:00
abstract：:Intercalative binding of the antitumor drugs amonafide and azonafide to the oligonucleotide duplex d(GGCCGGCCGG).d(CCGGCCGGCC) was compared using molecular dynamics in vacuum with the AMBER force field. A number of reasonable possible binding conformations were obtained, with the azonafide complexes favored over the a...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00402824
更新日期：1996-04-01 00:00:00
abstract：:As part of the fourth statistical assessment of modeling of proteins and ligands (sampl.eyesopen.com) prediction challenge, the strength of association of nine guests (1-9) binding to octa-acid host was determined by a combination of (1)H NMR and isothermal titration calorimetry. Association constants in sodium tetrab...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-013-9690-2
更新日期：2014-04-01 00:00:00
abstract：:When we build a predictive model of a drug property we rigorously assess its predictive accuracy, but we are rarely able to address the most important question, "How useful will the model be in making a decision in a practical context?" To answer this requires an understanding of the prior probability distribution ("t...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-010-9388-7
更新日期：2010-12-01 00:00:00
abstract：:Orientation of ten water molecules bound strongly at the contact surface of the dihydrofolate reductase-methotrexate enzyme-inhibitor complex was determined theoretically. To optimize the orientation of the water molecules, a recent method based on a simple electrostatic model was applied. The electrostatic complement...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF01532054
更新日期：1988-04-01 00:00:00
abstract：:Benchmarks for molecular docking have historically focused on re-docking the cognate ligand of a well-determined protein-ligand complex to measure geometric pose prediction accuracy, and measurement of virtual screening performance has been focused on increasingly large and diverse sets of target protein structures, c...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-011-9533-y
更新日期：2012-06-01 00:00:00
abstract：:New methods for docking, template fitting and building pseudo-receptors are described. Full conformational searches are carried out for flexible cyclic and acyclic molecules. QXP (quick explore) search algorithms are derived from the method of Monte Carlo perturbation with energy minimization in Cartesian space. An ad...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1007907728892
更新日期：1997-07-01 00:00:00
abstract：:All-atom molecular dynamics computer simulations were used to blindly predict the hydration free energies of a range of chloro-organic compounds as part of the SAMPL3 challenge. All compounds were parameterized within the framework of the OPLS-AA force field, using an established protocol to compute the absolute hydra...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-011-9527-9
更新日期：2012-05-01 00:00:00
abstract：:The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-li...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/b:jcam.0000021834.50768.c6
更新日期：2003-12-01 00:00:00
abstract：:In the present work we have modeled the Michaelis complex of the cyclic-Adenosine Monophosphate Dependent (cAMD) Protein Kinase A (PKA) with Mg(2)ATP and the heptapeptide substrate Kemptide by classical molecular dynamics. The chosen synthetic substrate is relevant for its high efficiency and small size, and it has no...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-007-9143-x
更新日期：2007-10-01 00:00:00
abstract：:The project on crystallographic modelling aims at extending the application of interactive graphics to inorganic structures. Starting from the available expertise in organic and protein modelling, the symmetry of the crystal structure is used not only to draw fixed models of many unit cells of the structure, which as ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF01531996
更新日期：1988-10-01 00:00:00
abstract：:SIRT1 is an NAD+-dependent deacetylase, whose activators have potential therapeutic applications in the age-related, metabolic, neurode-generative and cardiovascular diseases. Resveratrol (RSV) has been regarded as potent SIRT1 activator in the treatment of atherosclerosis and cardiovascular diseases. Moreover, the pr...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-019-00193-0
更新日期：2019-04-01 00:00:00
abstract：:The complex of adenylate kinase with its transition-state inhibitor has been studied by molecular dynamics simulations in water and in vacuum environments with the GROMOS force field over a period of 300 ps. The adenylate kinase, a member of the nucleotide-binding protein family, was exemplarily chosen for the inspect...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00125373
更新日期：1994-08-01 00:00:00
abstract：:An analysis of five different datasets of inhibitors of serotonin uptake has yielded quantitative structure/activity relationships (QSARs) which delineate the role of steric and hydrophobic properties essential for inhibition by phenylethylamine-type analogues. ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00125664
更新日期：1991-10-01 00:00:00
abstract：:The use of MP2 level quantum mechanical (QM) calculations on isolated heteroaromatic ring systems for the prediction of the tautomeric propensities of whole molecules in a crystalline environment was examined. A Polarisable Continuum Model was used in the calculations to account for environment effects on the tautomer...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-010-9345-5
更新日期：2010-06-01 00:00:00
abstract：:ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a histone lysine methyltransferase (HKMT) and it preferentially tri-methylates lysine 9 of histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are report...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0052-3
更新日期：2017-10-01 00:00:00
abstract：:Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxy lat e], Bay O 8495 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5- carboxylate], and Bay O 9507 [methyl 1,4-dihydr...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00129749
更新日期：1991-04-01 00:00:00
abstract：:A new method is presented for the calculation of the Molecular Electrostatic Potential (MEP) in large systems. Based on the mixed Quantum Mechanics/Molecular Mechanics (QM/MM) approach, the method assumes both a quantum and classical description for the molecule, and the calculation of the MEP in the space surrounding...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1008111820916
更新日期：2000-05-01 00:00:00
abstract：:AstexViewer is a Java molecular graphics program that can be used for visualisation in many aspects of structure-based drug design. This paper describes its functionality, implementation and examples of its use. The program can run as an Applet in a web browser allowing structures to be displayed without installing ad...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1023813504011
更新日期：2002-12-01 00:00:00
abstract：:The V2 vasopressin renal receptor (V2R), which controls antidiuresis in mammals, is a member of the large family of heptahelical transmembrane (7TM) G protein-coupled receptors (GPCRs). Using the automated GPCR modeling facility available via Internet (http:/(/)expasy.hcuge.ch/swissmod/SWISS-MODEL.+ ++html) for constr...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1007969526447
更新日期：1998-05-01 00:00:00
abstract：:The CASE (Computer Automated Structure Evaluation) program, with the aid of a geometry index for discriminating cis and trans isomers, has been used to study a set of retinoids tested for teratogenicity in hamsters. CASE identified 8 fragments, the most important representing the non-polar terminus of a retinoid with ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00125314
更新日期：1990-06-01 00:00:00
abstract：:In the absence of a 3D structure of the target biomolecule, to propose the 3D requirements for a small molecule to exhibit a particular bioactivity, one must supply both a bioactive conformation and a superposition rule for every active compound. Our strategy identifies both simultaneously. We first generate and optim...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00141577
更新日期：1993-02-01 00:00:00
abstract：:Macroscopic pKa values were calculated for all compounds in the SAMPL6 blind prediction challenge, based on quantum chemical calculations with a continuum solvation model and a linear correction derived from a small training set. Microscopic pKa values were derived from the gas-phase free energy difference between pro...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-018-0138-6
更新日期：2018-10-01 00:00:00
abstract：:In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-015-9880-1
更新日期：2015-12-01 00:00:00
