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PubMed2002

Computer-aided design of chiral ligands. Part I. Database search methods to identify chiral ligand types for asymmetric reactions.

The utility of database searching to identify chiral ligand motifs is outlined. The key elements of three known chiral ligands have been described as bond vectors. The CAVEAT program was then used to screen the Cambridge Structural Database (CSD), portions of the Chemical Abstracts Services three-dimensional database (CAS-3D), and the TRIAD tricyclic structure database for scaffolds containing these elements. Scaffolds corresponding to the known starting points were identified indicating that this method can be used to identify chiral ligand structural motifs. In addition, alternate structural motifs were found that suggested alternative possible ligands.

Boranes↗
PubMed2004

Computational protein design is a challenge for implicit solvation models.

Increasingly complex schemes for representing solvent effects in an implicit fashion are being used in computational analyses of biological macromolecules. These schemes speed up the calculations by orders of magnitude and are assumed to compromise little on essential features of the solvation phenomenon. In this work we examine this assumption. Five implicit solvation models, a surface area-based empirical model, two models that approximate the generalized Born treatment and a finite difference Poisson-Boltzmann method are challenged in situations differing from those where these models were calibrated. These situations are encountered in automatic protein design procedures, whose job is to select sequences, which stabilize a given protein 3D structure, from a large number of alternatives. To this end we evaluate the energetic cost of burying amino acids in thousands of environments with different solvent exposures belonging, respectively, to decoys built with random sequences and to native protein crystal structures. In addition we perform actual sequence design calculations. Except for the crudest surface area-based procedure, all the tested models tend to favor the burial of polar amino acids in the protein interior over nonpolar ones, a behavior that leads to poor performance in protein design calculations. We show, on the other hand, that three of the examined models are nonetheless capable of discriminating between the native fold and many nonnative alternatives, a test commonly used to validate force fields. It is concluded that protein design is a particularly challenging test for implicit solvation models because it requires accurate estimates of the solvation contribution of individual residues. This contrasts with native recognition, which depends less on solvation and more on other nonbonded contributions.

Algorithms↗
PubMed1986

Computer-assisted design of studies using routine clinical data. Analyzing the association of prednisone and cholesterol.

To facilitate the analysis of routine, longitudinal, clinical data, we developed a computer program called the RX Study Module. Our prototype uses a small online knowledge base of medicine and biostatistics to help create and execute a detailed statistical study design. The program identifies possible confounding variables, selects methods for controlling them, creates a statistical model, determines patient eligibility criteria, and retrieves data from records. We used the program to examine the hypothesis that daily prednisone administration elevates serum cholesterol. Data from 49 patients with chronic rheumatologic disorders were analyzed from a database of 1787 patients. A regression model was fitted to each patient's record. Changes in cholesterol were significantly correlated (p = 10(-5)) with changes in prednisone after a lag of at least 1 week and after recorded confounders were controlled: delta cholesterol = 18.4 loge(prednisone). Routinely collected patient data may become an important resource for generating and studying new medical hypotheses.

Artificial Intelligence↗
PubMed2001

Computer-assisted design of the sagittal shapes of a ligament-compatible total ankle replacement.

The poor results of total ankle replacement have been attributed to the inability of designers to restore adequately the critical mutual function of the ligaments and the articular surfaces. The purpose of this study was to design sagittal shapes of the articular surfaces for a new ankle prosthesis to be compatible with the geometry of the retained ligamentous structures. Several ligament-compatible pairs of articular surfaces were tested using a computerised version of a four-bar linkage model. The kinematics of the ankle when replaced by non-conforming two-component and by fully conforming three-component designs with either flat, concave or convex tibial surfaces were assessed by the model. A ligament-compatible convex-tibia fully-congruent three-component prosthesis showed the best features. The three-component prosthesis allows complete congruence over the entire range of flexion. A convex shape for the tibial arc was preferred because of the better degree of entrapment of the meniscal bearing. A 5 cm convex-tibia arc radius gave 2 mm entrapment together with 9.8 mm of tibial bone cut. Ligament elongation imposed by full congruence of the articular surfaces was less than 0.03% of the original length. The original patterns of joint kinematics and ligament tensioning are closely restored in the joint replaced by the proposed prosthesis.

Ankle Joint↗
PubMed2003

Computer-aided design of non sulphonyl COX-2 inhibitors: an improved comparative molecular field analysis incorporating additional descriptors and comparative molecular similarity indices analysis of 1,3-diarylisoindole derivatives.

A set of thirty five molecules of 1,3-diaryl-4,5,6,7-tetrahydro-2H-isoindoles endowed with selective COX-2 inhibitory activity was analyzed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Besides conventional steric and electrostatic fields, seven additional descriptors were incorporated to the CoMFA models. An improved CoMFA model (r(2)(cv)=0.536, r(2)(conv)=0.968, SEE=0.222, r(2)(pred)=0.6564) was obtained by taking into account the CMR as additional descriptor. This analysis provided useful information regarding the pharmacophoric requirements for COX-2 inhibitory activity. FlexX was used to find out the binding orientation of this new class of 1,3-diaryl isoindoles in the active site of COX-2. The contour maps produced by improved CoMFA model was superimposed onto the active site revealing a good correlation between the contour maps and the active site residue interactions.

Binding Sites↗
PubMed2005

Inherently chiral uranyl-salophen macrocycles: computer-aided design and resolution.

[structure: see text] A flipping motion rapidly inverts the bent structure of uranyl-salophen compounds and, consequently, causes fast enantiomerization of nonsymmetrically substituted derivatives. This process has been previously slowed by introducing bulky substituents in the imine bond region. Since the resulting complexes dissociate upon chromatographic treatment, an alternative approach to the design and synthesis of robust, nonflipping uranyl-salophen compounds is here described. Such an approach is based on the idea that the flipping motion would be blocked by connecting the para positions with respect to the phenoxide oxygens by means of polymethylene bridges of suitable length. Analysis of a number of uranyl-salophen compounds by molecular mechanics, while showing that bulky substituents in the imine bond region cause severe distortions of the ligand backbone, suggested that the best chain lengths are those that fit the gap between the phenoxide rings without altering the natural geometry of the parent uranyl-salophen compound. Calculations showed that such chains are those composed of 12 and 13 methylene units. Accordingly, chiral uranyl-salophen macrocycles bridged with 12- and 13-methylene chains were synthesized in fairly good yields and resolved by chiral HPLC.

Computer-Aided Design↗
PubMed2001

Simulation of carbohydrate-protein interactions: computer-aided design of a second generation GM1 mimic.

The oligosaccharide of ganglioside GM1 [Galbeta1-3GalNAcbeta1-4(NeuAcalpha2-3)Galbeta1-4Glcbeta1-1Cer] is the cellular target of two bacterial enterotoxins: the cholera toxin (CT) and the heat-labile toxin of E. coli (LT). We recently reported that the pseudosaccharide 2 [Galbeta1-3GalNAcbeta1-4(NeuAcalpha2-3)DCCHD] is a high-affinity ligand for CT. and thus a functional mimic of GM1 (Bernardi, A., Checchia, A., Brocca, P., Sonnino, S. and Zuccotto, F., J. Am. Chem. Soc., 121 (1999) 2032-2036). In this paper we describe the design of a second-generation mimic, formally obtained from 2 by inverting the configuration of a single stereocenter, thus transforming a N-acetyl galactosamine into a N-acetyl glucosamine. The design process involved modeling of the free ligand and its LT complex, followed by qualitative and quantitative comparison with the corresponding structures of 2. The protocol employed relied on both conformational search and molecular dynamics methodologies to account for the flexibility of both the ligand and the protein receptor. The conformational search of the LT:inhibitor complex showed that, compared to 2, the new compound can insert one more hydroxy group within the protein binding site. Molecular dynamics simulations showed that, in turn, this may trigger a series of rearrangements and reorientations of side chains and crystallographic water molecules in the toxin, leading to new H-bond contacts which may result in enhanced affinity of the new inhibitor. FEP calculations were performed by mutating the structure of 2 in solution and in the protein complex, and the prediction was made that the second-generation mimic should be a stronger binder than its parent compound.

Bacterial Toxins↗
PubMed2006

Computer-aided design of modular protein devices: Boolean AND gene activation.

Many potentially useful synthetic gene networks require the expression of an engineered gene if and only if two different DNA-binding proteins exist in sufficient concentration. While some natural and engineered systems activate gene expression according to a logical AND-like behavior, they often utilize allosteric or cooperative protein-protein interactions, rendering their components unsuitable for a toolbox of modular parts for use in multiple applications. Here, we develop a quantitative model to demonstrate that a small system of interacting fusion proteins, called a protein device, can activate an engineered gene according to the Boolean AND behavior while using only modular protein domains and DNA sites. The fusion proteins are created from transactivating, DNA-binding, non-DNA binding, and protein-protein interaction domains along with the corresponding peptide ligands. Using a combined kinetic and thermodynamic model, we identify the characteristics of the molecular components and their rates of constitutive production that maximize the fidelity of AND behavior. These AND protein devices facilitate the creation of complex genetic programs and may be used to create gene therapies, biosensors and other biomedical and biotechnological applications that turn on gene expression only when multiple DNA-binding proteins are simultaneously present.

Computer Simulation↗
PubMed1999

Stent design favorably influences the vascular response in normal porcine coronary arteries.

OBJECTIVES: The purpose of this study was to compare the arterial response following implantation of a stainless-steel, balloon-expandable, tubular slotted stent with that of a novel computer-designed, multi-cellular stent in normal porcine coronary arteries. BACKGROUND: Intracoronary stent placement has evolved into the primary strategy for percutaneous revascularization of symptomatic coronary arterial lesions. Presently there is intense interest in developing new stent designs to improve stent delivery and biocompatability. METHODS: Computer-assisted design was utilized to develop a balloon-expandable stent with symmetric expansion properties, uniform arterial wall coverage, longitudinal flexibility and radial strength. Quantitative coronary angiography and histological assessment of the stented arteries was used to evaluate the acute and chronic vascular responses to a stainless-steel, balloon-expandable, tubular slotted stent as compared to the computer-designed BX stent in the normolipemic swine. RESULTS: Forty stents (24 BX, 16 tubular slotted) were implanted in 19 miniature swine at a mean inflation pressure of 9 atm using identical delivery systems. Eight of the BX and none of the tubular slotted stents were post-dilated with a non-compliant balloon at 12-14 atm. The mean stent-to-artery ratio was similar for the BX (1.03 +/- 0.06) and tubular slotted (1.04 +/- 0.11; p = 0.59) designs. Protrusion or asymmetric radial flaring of a strut at the stent margin was present in 1 of 23 BX stents (4.3%) and 10 of 15 tubular slotted stents (66.7%; p < 0.0001). The mean arterial injury score was significantly less for the BX stent (0.2 +/- 0.2) as compared with the tubular slotted stents (0.4 +/- 0.4; p = 0.025). At 3 days, thrombus area was similar for the BX and tubular slotted designs (0.42 +/- 0.16 mm2 versus 0.44 +/- 0.18 mm2, respectively; p = 0.88). The mean neointimal area was significantly less for the BX at 2 months (1.09 +/- 0.25 mm2 versus 2.93 +/- 2.26 mm2 in the tubular slotted stent) and at 6 months (1.10 +/- 0.26 mm2 versus 2.07 +/- 0.65 mm2 in the tubular slotted stent; p = 0.01), resulting in approximately 50% less in-stent stenosis. CONCLUSIONS: The arterial response to a balloon-expandable stent can be favorably influenced by computer-assisted modification of design in an experimental model. Further study is warranted to determine the impact of stent design upon clinical in-stent restenosis.

Angioplasty, Balloon, Coronary↗
PubMed2003

Cholinesterase reactivation in vivo with a novel bis-oxime optimized by computer-aided design.

Recently, several bis-pyridiniumaldoximes linked by a variable-length alkylene chain were rationally designed in our laboratories as cholinesterase reactivators. Extensive in vitro tests of these oximes with acetylcholinesterase inhibited by two different organophosphate agents, echothiophate and diisopropylfluorophosphate, revealed one compound with particularly good reactivation kinetics and affinity for phosphorylated acetylcholinesterase (AChE). This compound, designated "ortho-7", with a heptylene chain bridging two aldoximes ortho to a pyridinium ring nitrogen, was chosen for detailed comparison with the classic reactivator pyridine-2-aldoxime methochloride (2-PAM). In vitro, ortho-7 reactivated AChE selectively, without restoring activity of the related enzyme butyrylcholinesterase (BChE). For in vivo studies, rats were injected with ortho-7 or 2-PAM before or after organophosphate exposure, and the activities of AChE and BChE were determined at multiple intervals in blood and solid tissues. Ortho-7 behaved nearly as well in the animal as in vitro, reactivating AChE to the same extent as 2-PAM in all peripheral tissues studied (serum, red blood cell, and diaphragm), but at doses up to 100-fold smaller. Like other oxime reactivators, ortho-7 did not reactivate brain AChE after systemic administration. Nonetheless, this agent could be useful in combination therapy for organophosphate exposure, and it may provide a platform for development of additional, even more effective reactivators.

Acetylcholinesterase↗
PubMed1991

Development and testing of protocols for computer-aided design of peptide drugs, using oxytocin.

Considerable clinical interest in neuropeptides and peptide hormones has stimulated recent research and development of peptide-based drugs. This process differs from most classical drug discovery procedures because peptide molecules have considerable inherent flexibility. In the present paper, to identify lowest energy and metastable conformers for drug design, and to develop protocols for such studies, conformational search algorithms, incorporating empirical energy calculations, have been applied in the analysis of the peptide oxytocin. Energy minimization in torsion angle space was carried out from a variety of starting conformations, including published structures, in all-atom mode and all with distance constraints for disulphide bond formation. The energy-minimized conformations have been further optimized by a mapping method. Complementary simulations have been performed in united-atom mode and a model representing the effects of water using dummy sites has been developed and tested for this representation. Several of the preferred conformers together with de novo conformations have been used as starting points in molecular dynamics simulations; 28 low potential energy conformations were located at a temperature of 4 K. Conformations are analysed to identify hydrogen bonds, phi-psi angle distributions and the RMS values relative to the X-ray structure of deamino-oxytocin. The modelled structure of lowest energy in the molecular mechanics calculations was also that of least RMS deviation from the crystal structure; whilst structures of lower energy but larger deviation were identified by molecular dynamics techniques. A metastable structure has been identified which satisfies existing criteria for the "active form", and this model is tested by a theoretical residue-substitution technique, to provide clues on the agonist/antagonist relationship at the atomic level.

Computers↗
PubMed2002

A comparison of a lecture and computer program to teach fundamentals of the Draw-a-Person test.

BACKGROUND: Although computer-assisted education has been used to augment education in many areas, there are few studies of programs designed to replace lectures in a medical curriculum. OBJECTIVE: To test whether a thoughtfully designed computer program can replace a standard lecture in a pediatrics curriculum while teaching the subject matter equally well. METHODS: A computer program was developed to teach the Draw-a-Person developmental test using the multimedia-authoring tool Director. One of us (A.E.C.) tested and modified the program several times during its creation after submitting it to several objective evaluators. Thirty-nine students taking the clinical pediatrics rotation were chosen by month to interact with the program or attend the lecture. All students then scored 3 drawings and assigned them a developmental age according to the Draw-a-Person test rules. Students assigned to the computer program also completed a questionnaire evaluating the program in several subjective areas. A t test for 2 samples assuming equal variance was used to analyze the test results. RESULTS: Students receiving the lecture (control group) scored the 3 drawings as 5.43 years (age range, 4.5-8 years), 9.08 years (age range, 7-12 years), and 3.5 years (age range, 2-5 years), respectively. Those using the computer program (study group) scored the 3 drawings as 5.91 years (age range, 5-7 years), 7.68 years (age range, 7-8 years), and 4.34 years (age range, 3-5 years), respectively. The correct answers for the ages were 6, 7.75, and 4.25 years, respectively. A t test for 2 samples assuming equal variance showed that students using the computer program performed better on all 3 drawings (P<.05, P<.02, and P<.002, respectively). CONCLUSIONS: Students using the computer program were more accurate than students attending the lecture when scoring drawings and estimating a developmental age from them. These results support the conclusion that a thoughtfully designed computer program can replace a standard lecture in a pediatrics curriculum.

Attitude to Computers↗
PubMed2005

HIV vaccine development by computer assisted design: the GAIA vaccine.

The design of epitope-driven vaccines that address the global variability of HIV has been significantly hampered by concerns about conservation of the vaccine epitopes across clades of HIV. We developed two computer-driven methods for improving epitope-driven HIV vaccines: the Epi-Assembler, which derives representative or "immunogenic consensus sequence" (ICS) epitopes from multiple viral variants, and VaccineCAD, which reduces junctional immunogenicity when epitopes are aligned in a string-of-beads format for insertion in a DNA expression vector. In this study, we report on 20 ICS HIV-1 peptides. The core 9-mer contained in these consensus peptides was conserved in 105-2250 individual HIV-1 strains. Nineteen of the 20 ICS epitopes (95%) evaluated in this study were confirmed in ELISpot assays using peripheral blood monocytes obtained from 13 healthy HIV-1 infected subjects. Twenty-five ICS peptides (all 20 of the peptides evaluated in this study and 5 additional ICS epitopes) were then aligned in a pseudoprotein string using "VaccineCAD", an epitope alignment tool that eliminates immunogenicity created by the junctions between the epitopes. Reordering the construct reduced the immunogenicity of the junctions between epitopes as measured by EpiMatrix, an epitope mapping algorithm. The reordered construct was also a more effective immunogen in vivo when tested in HLA-DR transgenic mice. These data confirm the utility of bioinformatics tools to design novel vaccines containing "immunogenic consensus sequence" T cell epitopes for a globally relevant vaccine against HIV.

AIDS Vaccines↗
PubMedDate not supplied

The integration of theoretical constructs into the design of computer assisted instruction.

The authors believe that for computer assisted instruction to be an effective instructional tool, it must incorporate the most current theoretical principles related to learning and instruction. To assist future developers of computer assisted instruction, the authors review some of the major constructs from the theoretical foundations of various disciplines and then illustrate the integration of these constructs in the design of a software program entitled SOS--Strategies for Problem Solving.

Computer-Assisted Instruction↗
PubMed1997

Hemodynamic simulations and computer-aided designs of graft-artery junctions.

Severe occlusion of graft-artery junctions due to restenosis, e.g., excessive tissue overgrowth and renewed plaque formation, may occur within a few months or years after bypass surgery. Our hypothesis is that nonuniform hemodynamics, represented by large sustained wall shear stress gradients, trigger abnormal biological processes leading to rapid restenosis and hence early graft failure. In turn, this problem may be significantly mitigated by designing graft-artery bypass configurations for which the wall shear stress gradient (WSSG) is approximately zero and hence nearly uniform hemodynamics are achieved. Focusing on the distal end of several femoral artery bypass junctions, a validated finite volume code has been used to compute the transient three-dimensional velocity vector fields and its first and second surface derivatives in order to test the idea. Specifically, it is shown that the Taylor patch, which generates higher patency rates than standard end-to-side anastomoses, exhibits lower WSSG levels than standard configurations, and that further geometric design improvements reduce the WSSG in magnitude and local extent even more.

Algorithms↗