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PubMed2003

Strategy of computer-aided drug design.

Modern strategies of computer-aided drug design (CADD) are reviewed. The task of CADD in the pipeline of drug discovery is accelerating of finding the new lead compounds and their structure optimization for the following pharmacological tests. The main directions in CADD are based on the availability of the experimentally determined three-dimensional structure of the target macromolecule. If spatial structure is known the methods of structure-based drug design are used. In the opposite case the indirect methods of CADD based on the structures of known ligands (ligand-based drug design) are used. The interrelationship between the main directions of CADD is reviewed. The main CADD approaches of molecule de novo design and database mining are described. They include methods of molecular docking, de novo design, design of pharmacophore and quantity structure-activity relationship models. New ways and perspectives of CADD are discussed.

Computational Biology↗
PubMed1988

Evaluation of a digitizer and computer system designed to analyze articulator-generated occlusal tracings.

Occlusal tracings generated on a Denar fully adjustable articulator were photographed, projected, digitized, and stored in a computer data file. These steps were accomplished with sufficient accuracy for clinical analysis. This study demonstrated that appropriately referenced tracing data can be transferred accurately into a machine-readable form. Studies of pantographic tracings for mandibular movements are facilitated by this convenient and accurate method of handling data.

Dental Articulators↗
PubMedDate not supplied

[Computer drug design based on analysis of a target macromolecule structure. I. Search and description of a ligand binding site in a target molecule].

The applicability of molecular docking method for finding of ligand binding site in a target protein was tested. The basic principle of tested approach consists in generation of hypotheses of protein-ligand complexes by molecular docking of small ligand to all surface of protein. The subsequent scoring of these hypotheses utilizes the values of contact surfaces and complex formation energy. The docking procedure was executed using the original software DockSearch running on PC Pentium or SGI computers. A set of hypotheses of probable ligand positions on the protein surface was created and evaluated with the help of DockSearch. Energy minimization of molecular complexes was done using Sybyl 6.5 (Tripos Inc.) running on SGI server Origin 200. The final set of the best hypotheses of complexes were selected by the values of contact surfaces and complex formation energy. The applicability and the limits of this approach was tested using known 3D structures of different proteins in free state and in complexes with ligands. For most target proteins the method allows to find the ligand binding site correctly. The accuracy of description of ligand binding site is adequate for subsequent searching of lead compounds by database mining. The reasons of some negative results obtained in testing of this approach are also discussed.

Binding Sites↗
PubMed2002

Computer-based design of an HLA-haplotype and HIV-clade independent cytotoxic T-lymphocyte assay for monitoring HIV-specific immunity.

BACKGROUND: Human immunodeficiency virus (HIV)- specific CD8-positive cytotoxic T-lymphocytes (CTL) play a key role in controlling HIV infection. Monitoring CTL response could be clinically relevant during structured therapy interruption (STI), HIV exposure, and vaccine trials. However, HLA patients' restriction and HIV variability limited the development of a CTL assay with broad specificity. MATERIALS AND METHODS: We designed an HLA-class I/HIV-1 clade independent assay for assessing HIV- specific CTL by using a computer-assisted selection ofthe CTL epitopes. Twenty-eight 15-mers were selected by peptide-binding motifs analysis using different databases (HIV-Immunology Database, SYFPEITHI, BIMAS). Altogether they putatively bind to more than 90% of HLA haplotypes in different populations, with an overall HIV-1 variability below 9%. The peptide pool was used as an antigen in an intracellular cytokine staining (ICS) assay for quantifying HIV-specific CTL response. RESULTS: The test can be performed using both fresh and cryopreserved peripheral blood mononuclear cells (PBMC), whereas GAG protein as antigen works only on fresh PBMC. A significantly higher CTL response with respect to HIV-negative controls was detected in all HIV-1 infected subjects of two groups of patients with different ethnicities (Caucasians and Africans) and coming from areas with different HIV-1 clade prevalences (clade B and A/G, respectively). In Caucasian patients, after month of STI, the number of HIV-1 specific CTL (2,896 +/- 2,780 IFN-gamma specific CD8 cells/ml) was significantly higher than that found at enrolment (2,125 +/- 4,426 IFN-gamma specific CD8 cells/ml, p< 0.05). CONCLUSIONS: These data indicate that this CTL assay is broadly specific and could represent a useful clinical tool for HIV immunodiagnostic independent of HLA-haplotype and HIV-clade variabilities.

Adult↗
PubMed2003

Field interaction and geometrical overlap: a new simplex and experimental design based computational procedure for superposing small ligand molecules.

Alignment of molecules is a crucial and time-consuming step in any 3D-QSAR study. For this reason, the field interaction and geometrical overlap (FIGO) procedure presented in this paper is particularly relevant because it can provide an objective and automatic superposition of ligands through the computation of an appropriate alignment index (AI). Ligand overlay takes place via a simplex optimization of the AI function. Experimental design strategies (full factorial design, D-optimal design) are used to define the starting positions of the superposing molecules. Overlay experiments are carried out to test the performance of the method. Comparison between the results obtained with FIGO and known ligand-receptor X-ray crystallographic data (Protein Data Bank) suggests that FIGO is an effective and reliable computational procedure.

Benzene Derivatives↗
PubMed2000

Computer-aided design and activity prediction of leucine aminopeptidase inhibitors.

The Ligand Design (LUDI) approach has been used in order to design leucine aminopeptidase inhibitors, predict their activity and analyze their interactions with the enzyme. The investigation was based on the crystal structure of bovine lens leucine aminopeptidase (LAP) complexed with its inhibitor--the phosphonic acid analogue of leucine (LeuP). More than 50 potential leucine aminopeptidase inhibitors have been obtained, including the most potent aminophosphonic LAP inhibitors with experimentally known activity, which have been the subject of more detailed studies. A reasonable agreement between theoretical and experimental activities has been obtained for most of the studied inhibitors. Our results confirm that LUDI is a powerful tool for the design of enzyme inhibitors as well as in the prediction of their activity. In addition, for inhibitor-active site interactions dominated by the electrostatic effects it is possible to improve binding energy estimates by using a more accurate description of inhibitor charge distribution.

Animals↗
PubMedDate not supplied

Computer-aided design of novel siderophores: pyridinochelin.

Pyridinochelin, a novel tetradentate catecholate-type siderophore, has been designed on the basis of the active analog enterobactin and was then synthesized. Growth promotion tests indicate that this synthetic siderophore feeds various pathogenic bacteria most effectively with iron even though it lacks one catecholate group compared to enterobactin. The superposition of the mentioned siderophore structures suggests that the structure of the skeleton connecting the catecholate groups might be an important factor for the iron transport.

Bacteria↗
PubMed2000

Computer-aided design, synthesis and biological assay of p-methylsulfonamido phenylethylamine analogues.

Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Based on our previous studies, a set of 17 methylsulfonamido phenylethylamine analogues were investigated by 3D-QSAR techniques of CoMFA and CoMSIA. The 3D-QSAR models proved a good predictive ability, and could describe the steric, electrostatic and hydrophobic requirements for recognition forces of the receptor site. According to the clues provided by this 3D-QSAR analysis, we designed and synthesized a series of new analogues of methanesulfonamido phenylethylamine (VIa-i). Pharmacological assay indicated that the effective concentrations of delaying the functional refractory period (FRP) 10ms of these new compounds have a good correlation with the 3D-QSAR predicted values. It is remarkable that the maximal percent change of delaying FRP in microM of compound VIc is much higher than that of dofetilide. The results showed that the 3D-QSAR models are reliable.

Animals↗
PubMed1995

Computer-aided design and synthesis of 5-substituted tryptamines and their pharmacology at the 5-HT1D receptor: discovery of compounds with potential anti-migraine properties.

The design and synthesis of a series of novel 5-substituted tryptamines with pharmacological activity at 5-HT1D and other monoamine receptors is described. Structural modifications of N- and C-linked (principally hydantoin) analogues at the 5-position were synthesized and their pharmacological activities were utilized to deduce significant steric and electrostatic requirements of the 5-HT1D and 5-HT2A receptor subtypes. Conformations of the active molecules were computed which, when overlaid, suggested a pharmacophore hypothesis which was consistent with the affinity and selectivity measured at 5-HT1D and 5-HT2A receptors. This pharmacophore is composed of a protonated amine site, an aromatic site, a hydrophobic pocket, and two hydrogen-bonding sites. A "selectivity site" was also identified which, if occupied, induced sensitivity for 5-HT1D over 5-HT2A in this series of molecules. The development and use of the pharmacophore models in compound design is described. In addition, the physicochemical constraints of molecular size and hydrophobicity required for efficient oral absorption are discussed. Utilizing the pharmacophore model in conjunction with the physicochemical constraints of molecular size and log DpH7.4 led to the discovery of 311C90 (6), a new selective 5-HT1D agonist with good oral absorption and potential use in the treatment of migraine.

Animals↗
PubMed2004

A database designed to computationally aid an experimental approach to alternative splicing.

A unique microarray approach has been developed to profile alternative splicing in the cell. To support the development of this approach, we have developed the Manually Annotated Alternatively Spliced Events (MAASE) database system, which is a unique alternative splicing information resource designed specifically with experimentalists in mind. MAASE is an online resource for the convenient access, identification, and annotation of alternative splicing events (ASEs). MAASE consists of two components: an annotation system and a curated database. The annotation system is a web-based workspace that combines manual and computational approaches to identifying and annotating ASEs, a combination that is vital if a comprehensive collection is to be obtained. The annotation system is publicly available and provides a scalable solution to acquiring as well as contributing to annotated ASEs. MAASE annotated ASEs are deposited into the database component, which can either be queried one entry at a time or multiple entries at a time with convenient access to alternatively spliced junctional and surrounding sequences to facilitate the design of microarray experiments.

Alternative Splicing↗
PubMed2003

[Spatial and temporal characteristic of eye movement in human-computer interface design].

OBJECTIVE: To examine the related spatial and temporal characteristics of eye movement in HCI design and to provide ergonomic parameters to optimize the HCI design based on eye tracking. METHOD: Task time, selected error and timeout numbers were recorded automatically, when 12 participants were performing the task of target selection, with different object size, space and dwell time. RESULT: It was significantly found that task time was influenced by object size and dwell time, the selected error was influenced by object space and dwell time significantly. CONCLUSION: The dwell time, object size and object space are all important to optimize the HCI design based on eye tracking. We recommend that the dwell time should be 500 ms, the object size and object space should be not less than 1.5 degrees and 1.0 degrees respectively for the normal interactive systems.

Adult↗
PubMed1986

[Computer-assisted design and production of a femoral hip prosthesis].

The authors believe that a better design of prosthetic femoral stem might reduce the incidence of loosening. They have developed a method to make a prosthesis precisely adapted to a patient. Two X-Rays, one antero-posterior and one lateral view are taken. Several bony points are precisely determined. The magnification of the X-Rays is calculated, using a metallic circular collar placed around the thigh. A computer analyses the X-Rays, bony points are numerated and the prostheses have a length, thickness and shape adapted to the patient's hip. A study of the pressures transmitted by the prostheses to the bone was made using geometrical models. Compared to conventional prostheses, a prosthesis made as an exact fit to the hip of the patient reduces the pressure applied on femoral cortex by two thirds. A prosthesis with a collar also allows reduction of pressure on the cortex by a degree of three to one. The personalized prosthesis obtained by the use of a computer appears to be a stage in progress towards a better fitting and more reliable prosthesis. Twenty five patients have been operated on with good short-term results.

Computers↗
PubMed2001

Design, synthesis, computational prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii.

A series of lipophilic soft drugs structurally related to the nonclassical dihydrofolate reductase (DHFR) inhibitors trimetrexate and piritrexim have been designed, synthesized, and evaluated in DHFR assays, with special emphasis on the inhibition of P. carinii DHFR. The best inhibitors, encompassing an ester bond in the bridge connecting the two aromatic systems, were approximately 10 times less potent than trimetrexate and piritrexim. The metabolites were designed to be poor inhibitors. Furthermore, molecular dynamics simulations of three ligands in complex with DHFR from Pneumocystis carinii and from the human enzyme were conducted in order to better understand the factors determining the selectivity. A correct ranking of the relative inhibition of DHFR was achieved utilizing the linear interaction energy method. The soft drugs are intended for local administration. One representative ester was selected for a pharmacokinetic study in rats where it was found to undergo fast metabolic degradation to the predicted inactive metabolites.

Animals↗