Abstract:
:A theoretical conformational study was performed on leu-enkephalin in its zwitterionic form, both in vacuo and in the presence of a number, n, of up to 13 water molecules saturating its first hydration shell. The intramolecular energy of enkephalin as well as the intermolecular enkephalin-water and water-water interaction energies were computed with the SIBFA procedure (Sum of Interactions Between Fragments Ab initio computed), which uses additive ab initio multipole systematics and analytical formulas grounded on ab initio SCF computations. Energy minimizations were performed with a polyvalent minimizer, Merlin, with which three distinct derivative and three distinct nonderivative minimizers can be activated in a sequential fashion. Eight different candidate conformations of enkephalin were used as starting points. These conformations are either those found in distinct X-ray structures, or those proposed on the basis of theoretical computations by other authors. In the absence of hydration, they converged towards distinct folded energy-minima, the best four ones being separated by an energy gap of 8.7 kcal/mol. In marked contrast, with up to n = 13, the energetical separation between the six best conformers narrowed down to congruent to 4 kcal/mol. They can be characterized by: (a) either a direct or a water-mediated ammonium-carboxylate interaction; b) either a close proximity (as in morphine) or a large separation between the aromatic rings of Tyr and Phe (intercenter separations of congruent to 4.5 A and congruent to 10.5 A, respectively), with each of the four mutual combinations of (a) and (b) being represented.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Demetropoulos IN,Gresh Ndoi
10.1007/BF00129748subject
Has Abstractpub_date
1991-04-01 00:00:00pages
81-94issue
2eissn
0920-654Xissn
1573-4951journal_volume
5pub_type
杂志文章abstract::Ligand efficiency metrics are used in drug discovery to normalize biological activity or affinity with respect to physicochemical properties such as lipophilicity and molecular size. This Perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of protein-ligand binding. Different cl...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9757-8
更新日期:2014-07-01 00:00:00
abstract::Non-canonical base pairs contribute immensely to the structural and functional variability of RNA, which calls for a detailed characterization of their spatial conformation. Intra-base pair parameters, namely propeller, buckle, open-angle, stagger, shear and stretch describe structure of base pairs indicating planarit...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-006-9083-x
更新日期:2006-10-01 00:00:00
abstract::This paper describes several case studies concerning protein function inference from its structure using our novel approach described in the accompanying paper. This approach employs family-specific motifs, i.e. three-dimensional amino acid packing patterns that are statistically prevalent within a protein family. For...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-009-9277-0
更新日期:2009-11-01 00:00:00
abstract::Optimization in medicinal chemistry often involves designing replacements for a section of a molecule which aim to retain potency while improving other properties of the compound. In this study, we perform a retrospective analysis using a number of computational methods to identify active side chains amongst a pool of...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00313-1
更新日期:2020-09-01 00:00:00
abstract::A structure-binding activity relationship for the intestinal bile acid transporter has been developed using data from a series of bile acid analogs in a comparative molecular field analysis (CoMFA). The studied compounds consisted of a series of bile acid-peptide conjugates, with modifications at the 24 position of th...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1007919704457
更新日期:1997-11-01 00:00:00
abstract::While it may seem intuitive that using an ensemble of multiple conformations of a receptor in structure-based virtual screening experiments would necessarily yield improved enrichment of actives relative to using just a single receptor, it turns out that at least in the p38 MAP kinase model system studied here, a very...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-008-9182-y
更新日期:2008-09-01 00:00:00
abstract::The de novo design program Skelgen has been used to design inhibitor structures for four targets of pharmaceutical interest. The designed structures are compared to modeled binding modes of known inhibitors (i) visually and (ii) by means of a novel similarity measure considering the size and spatial proximity of the m...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1021242018286
更新日期:2002-07-01 00:00:00
abstract::Cytochrome P450 (CYP) enzymes play an important role in the metabolism of xenobiotics. Since they are connected to drug interactions, screening for potential inhibitors is of utmost importance in drug discovery settings. Our study provides an extensive classification model for P450-drug interactions with one of the mo...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00308-y
更新日期:2020-08-01 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::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::This paper tests the performance of a simple empirical scoring function on a set of candidate designs produced by a de novo design package. The scoring function calculates approximate ligand-receptor binding affinities given a putative binding geometry. To our knowledge this is the first substantial test of an empiric...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008040323669
更新日期:1998-09-01 00:00:00
abstract::To generate reduced point charge models of proteins, we developed an original approach to hierarchically locate extrema in charge density distribution functions built from the Poisson equation applied to smoothed molecular electrostatic potential (MEP) functions. A charge fitting program was used to assign charge valu...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-011-9471-8
更新日期:2011-10-01 00:00:00
abstract::It is essential, in order to minimise expensive drug failures due to toxicity being found in late development or even in clinical trials, to determine potential toxicity problems as early as possible. In view of the large libraries of compounds now being handled by combinatorial chemistry and high-throughput screening...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章,评审
doi:10.1023/a:1025361621494
更新日期:2003-02-01 00:00:00
abstract::Quantitative Structure-Activity Relationship (QSAR) models are used increasingly to screen chemical databases and/or virtual chemical libraries for potentially bioactive molecules. These developments emphasize the importance of rigorous model validation to ensure that the models have acceptable predictive power. Using...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1025386326946
更新日期:2003-02-01 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::Anaplastic lymphoma kinase (ALK) has been thought to be a prospective target of anti-drug resistance design in treatment of tumors and specific neuron diseases. It is highly useful for the seeking of possible strategy alleviating drug resistance to probe the mutation-mediated effect on binding of inhibitors to ALK. In...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00355-5
更新日期:2020-12-01 00:00:00
abstract::Aligning and overlaying two or more bio-active molecules is one of the key tasks in computational drug discovery and bio-activity prediction. Especially chemical-functional molecule characteristics from the view point of a macromolecular target represented as a 3D pharmacophore are the most interesting similarity meas...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-006-9078-7
更新日期:2006-12-01 00:00:00
abstract::A series of non-peptide angiotensin II receptor antagonists was investigated with the aim of developing a 3D QSAR model using comparative molecular field analysis descriptors and approaches. The main goals of the study were dictated by an interest in methodologies and an understanding of the binding requirements to th...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00134180
更新日期:1996-12-01 00:00:00
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 t...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/b:jcam.0000022559.72848.1c
更新日期:2004-01-01 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::Furanopyrimidine 1 (IC50 = 273 nM, LE = 0.36, LELP = 10.28) was recently identified by high-throughput screening (HTS) of an in-house library (125,000 compounds) as an Aurora kinase inhibitor. Structure-based hit optimization resulted in lead molecules with in vivo efficacy in a mouse tumour xenograft model, but no or...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9807-2
更新日期:2015-01-01 00:00:00
abstract::Learning strategies can be used to improve the efficiency of virtual screening of very large databases. In these strategies new compounds to be screened are selected on the basis of the results obtained in previous stages, even if truly good ligands have not yet been identified. This approach requires that the scoring...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-008-9246-z
更新日期:2009-03-01 00:00:00
abstract::Glucokinase (GK) is involved in normal glucose homeostasis and therefore it is a valid target for drug design and discovery efforts. GK activators (GKAs) have excellent potential as treatments of hyperglycemia and diabetes. The combined recent interest in GKAs, together with docking limitations and shortages of dockin...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9740-4
更新日期:2014-05-01 00:00:00
abstract::Toxoplasma (T.) gondii, the causative agent of toxoplasmosis, is a ubiquitous opportunistic pathogen that infects individuals worldwide, and is a leading cause of severe congenital neurologic and ocular disease in humans. No vaccine to protect humans is available, and hypersensitivity and toxicity limit the use of the...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-011-9420-6
更新日期:2011-05-01 00:00:00
abstract::The worldwide spread of beta-lactamases with hydrolytic activity extended to last resort carbapenems is aggravating the antibiotic resistance problem and endangers the successful antimicrobial treatment of clinically relevant pathogens. As recently highlighted by the World Health Organization, new strategies to contai...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-018-0182-2
更新日期:2019-02-01 00:00:00
abstract::We describe the performance of multiple pose prediction methods for the D3R 2016 Grand Challenge. The pose prediction challenge includes 36 ligands, which represent 4 chemotypes and some miscellaneous structures against the FXR ligand binding domain. In this study we use a mix of fully automated methods as well as hum...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-017-0053-2
更新日期:2018-01-01 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::Several chiral vinylboranes have been theoretically evaluated as enantioselective Diels-Alder dienophiles. Theoretical results suggest that optically pure 2,5-diphenyl-1-vinyl-borolane should be the reagent of choice for performing such transformations efficiently. ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/b:jcam.0000035200.30340.41
更新日期:2004-03-01 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::Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational changes in the E protein and is an essential step in the virus li...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-009-9263-6
更新日期:2009-06-01 00:00:00