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PubMed1992

Computer-aided drug design: getting the best results.

There are two major stages in the design of drug molecules: lead-molecule development and lead-molecule optimization. Whereas a variety of computational chemistry and molecular modeling (CC/MM) techniques are now routinely and successfully applied to the optimization stage of drug design, the generation of initial lead compounds has proven a more difficult problem for the CC/MM approach. Only recently has the design of lead molecules by this route become a subject of active research. This article looks at the factors which must be considered carefully when incorporating CC/MM methods into different aspects of drug-design strategies.

Computers↗
PubMed1991

[Computer-Aided Drug Design: An Alternative to Animal Testing in the Pharmacological Screening]

By means of graphical and numerical simulation of the binding of a biological key molecule to a receptor, Computer-Aided Drug Design (CADD) allows the semi-quantitative prediction of the activity of potential drug molecules. New drugs can be tailor-made for a specific receptor without animal testing; substances with little or no pharmacological activity are unambiguously identified and removed from the evaluation process before preclinical "in vivo" tests become necessary. Two methods, direct CADD and Receptor Mapping are presented.

Journal Article↗
PubMed2002

Performance evaluation of an 85-cm-bore X-ray computed tomography scanner designed for radiation oncology and comparison with current diagnostic CT scanners.

INTRODUCTION: The demand for computed tomography (CT) virtual simulation is constantly increasing with the wider adoption of three-dimensional conformal and intensity-modulated radiation therapy. Virtual simulation CT studies are typically acquired on conventional diagnostic scanners equipped with an external patient positioning laser system and specialized planning and visualization software. Virtual simulation technology has matured to a point where conventional simulators may be replaced with CT scanners. However, diagnostic CT scanner gantry bores (typically 65-70 cm) can present an obstacle to the CT simulation process by limiting patient positions, compared to those that can be attained in a conventional simulator. For example, breast cancer patients cannot always be scanned in the treatment position without compromising reproducibility and appropriateness of setup. Extremely large patients or patients requiring special immobilization or large setup devices are often unable to enter the limited-bore gantry. A dedicated 85-cm-bore radiation oncology CT scanner has the potential to eliminate these problems. The scanner should provide diagnostic-quality images at diagnostic-comparable dose levels. The purpose of this study was to independently evaluate the performance of a novel 85-cm-bore CT X-ray scanner designed specifically for radiation oncology and compare it against diagnostic-type, 70-cm-bore scanners that may be used in the same setting. MATERIALS AND METHODS: We performed image quality and dosimetric measurements on an 85-cm-bore CT scanner (AcQSim CT, Marconi Medical Systems, Inc., Cleveland, OH) and a 70-cm-bore, diagnostic-type scanner (UltraZ CT, Marconi Medical Systems, Inc.). Image quality measurements were performed using a manufacturer-supplied phantom (Performance Phantom, Marconi Medical Systems, Inc.), following the manufacturer's suggested testing procedures, and an independent image quality phantom (CATPHAN 500, The Phantom Laboratory, New York, NY). The standard image quality parameters evaluated for the purpose of comparison were as follows: slice thickness accuracy, high-contrast resolution (limiting spatial resolution), low-contrast resolution, uniformity and noise, and CT number accuracy and linearity. Standard head and body protocols were employed throughout most of our measurements and were kept equal between the two scanners. The computed tomography dose index was measured for standard head and body imaging protocols using accepted methods and procedures. For comparison purposes, data for a diagnostic-type, 70-cm-bore scanner (GE HighSpeed CT/i) were extracted from the literature. The results obtained for the 85-cm-bore scanner are compared with the following: (1) manufacturer-provided autoperformance phantom test results (validating its use for routine quality assurance), (2) a similar set of measurements performed on a conventional 70-cm-bore, diagnostic-type CT scanner (UltraZ CT, Marconi Medical Systems, Inc.), and (3) current available data on other diagnostic-type CT scanners (GE HighSpeed CT/i). RESULTS: Head and body doses seem on average to be slightly (1-2 cGy) higher for the 85-cm-bore unit than for conventional 70-cm units. Measured slice thickness was within acceptable criteria, +/-0.5 mm. There does not seem to be any significant difference in high-contrast resolution. Both units render a limiting value of approximately 7-8 lp/cm for slice thickness 8-10 mm. Both units exhibit comparable CT number uniformity, accuracy, and linearity. Noise levels seem to be slightly increased (by approximately 0.05-0.2%) for the large-bore geometry. Low-contrast resolution for both units was comparable (4.5-5.5 mm @ 0.35%). All image quality parameters are well within diagnostic acceptable levels. CONCLUSION: The overall imaging performance and mechanical integrity of the 85-cm-bore scanner are comparable to those of conventional diagnostic scanners that may be employed in a radiation oncology setting.

Computer Simulation↗
PubMed1984

The design of a computer-assisted education system using a CT scanner computer.

The minicomputer that is part of a commercial CT scanner has been used to develop a general purpose computer-assisted education system. This allows instruction in radiology using the CT computer already installed in the radiology department. The computer software was designed as a course interpreter, allowing the courses themselves to be written in English. Images and educational text are stored on separate disk files and displayed by the interpreter.

Computer-Assisted Instruction↗
PubMed2004

Volumetric spinal canal intrusion: a comparison between thoracic pedicle screws and thoracic hooks.

STUDY DESIGN: A computer-aided design analysis. OBJECTIVES: To introduce the concept of volumetric spinal canal intrusion and report the relative intrusion volumes for thoracic pedicle screws compared to thoracic laminar and pedicle hooks. SUMMARY OF BACKGROUND DATA: Thoracic pedicle screws are being used more frequently; however, there is concern about neurologic risk from medial misplacement. The accepted alternative to screws is hooks. Laminar and pedicle hooks also have significant obligatory spinal canal intrusion. To date, there have been no comparison studies. METHODS: Volumetric analysis of canal intrusion of pedicle screws and hooks was performed by computer-aided design CAM. All implants were of a single product line by a single manufacturer (CD Horizon M8, Medtronic Sofamor Danek). Intrusion of pedicle screws with medial positioning was analyzed in 0.5-mm increments, including a calculation of the "screw shadow," representing additional space not available for the spinal cord between screw threads and lateral to a medially positioned screw with intrusion greater than the screw radius. The length of screw intrusion was determined from postoperative CT scans in patients with thoracic pedicle screw instrumentation. All hook styles were analyzed. The volume of the footplate in line with the dorsal surface of the footplate was considered the intruding volume for laminar hooks, with increasing offset in 0.25-mm increments to represent imperfect fit. Half of the volume of the footplate was considered to be the intruding volume for pedicle hooks since a properly positioned pedicle hook straddles the pedicle. RESULTS: Volumetric intrusion for a 4.5-mm screw ranged from 2.2 mm3 (0.5 mm medial perforation) to 83.4 mm3 (3.0 mm perforation). For a 5.5-mm screw, intrusion volume range was from 1.3 mm3 to 83.2 mm3. Accounting for the "screw shadow," the volumetric intrusion was 9.83 mm3 to 116.3 mm3 and 10.88 mm3 to 134.89 mm3, respectively. Hook volumetric intrusion ranged from 21.15 mm3 for a pediatric narrow-blade ramped pedicle hook to 113.9 mm3 for a wide-blade laminar hook with 1.0 mm of step-off. CONCLUSIONS: A 4.5-mm or 5.5-mm thoracic pedicle screw must have a medial perforation of >or=1.5 mm to have the same volumetric spinal canal intrusion as a pediatric narrow-blade pedicle hook, the smallest hook footplate. Further, the medial violation must be >3 mm to approach the same volumetric intrusion as the largest hook. Accounting for the "screw shadow," a thoracic pedicle screw must have a medial perforation of >2 mm to approach the same intrusion volume as a standard pedicle hook. In the absence of direct neural injury, this explains the clinical finding of medial perforation of up to 4 mm without neurologic compromise.

Animals↗
PubMedDate not supplied

Concept design of computer-aided study on traditional Chinese drugs.

Traditional Chinese drugs (TCDs) have played a key role for Chinese people in the treatment of diseases since ancient times. The use of TCDs has generated a great amount of information in the past thousand years about the relationship between natural products and the human body. However, up to now, our understanding on the mode of action of the TCD is still limited. Considering that the basic mechanism of all drug function involves the interaction between the drug and biological receptors at the molecular level, we propose to connect TCDs with modern medicine theory through molecular structures. We propose to explain functions of TCDs by using the knowledge developed in modern molecular biology, pharmacology, computer chemistry, and biochemistry. We are working on a computer-aided Chinese drug study that is discussed in this paper. A short introduction on the progress of our research is also given.

Artificial Intelligence↗
PubMedDate not supplied

Soft computing in the design of nontoxic chemicals.

This research focuses on the use of soft computing to aid in the development of novel, state-of-the-art, nontoxic dyes which are of commercial importance to the U.S. textile industry. Where appropriate, modern molecular orbital (MO) and density functional (DF) techniques are employed to establish the necessary databases of molecular properties to be used in conjunction with the neural network approach. In this research, we focused on the following: (1) using molecular modeling to establish databases of various molecular properties of azo dyes required as input for our neural network approach; (2) designing and implementing a neural network architecture suitable to process these databases; and (3) investigating combinations of molecular descriptors needed to predict various properties of the azo dyes.

Journal Article↗
PubMed2005

Computational manufacturing as a bridge between design and production.

Computational manufacturing of optical coatings is a research area that can be placed between theoretical designing and practical manufacturing in the same way that computational physics can be placed between theoretical and experimental physics. Investigations in this area have been performed for more than 30 years under the name of computer simulation of manufacturing and monitoring processes. Our goal is to attract attention to the increasing importance of computational manufacturing at the current state of the art in the design and manufacture of optical coatings and to demonstrate possible applications of this research tool.

Journal Article↗
PubMed2006

Design, synthesis, and computational studies of inhibitors of Bcl-XL.

One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of Bcl-2 family proteins, we found a unique folded conformation adopted by tethered aromatic groups in the ligand that significantly enhanced binding affinity to Bcl-XL. This finding led us to design compounds that were biased by nonbonding interactions present in a urea tether to adopt this bioactive, folded motif. To characterize the key interactions that induce the desired conformational bias, a series of substituted N,N'-diarylureas were prepared and analyzed using X-ray crystallography and quantum mechanical calculations. Stabilizing pi-stacking interactions and destabilizing steric interactions were predicted to work in concert in two of the substitution patterns to promote the bioactive conformation as a global energy minimum and result in a high target binding affinity. Conversely, intramolecular hydrogen bonding present in the third substitution motif promotes a less active, extended conformer as the energetically favored geometry. These findings were corroborated when the inhibition constant of binding to Bcl-XL was determined for fully elaborated analogues bearing these structural motifs. Finally, we obtained the NMR solution structure of the disubstituted N,N'-diarylurea bound to Bcl-XL demonstrating the folded conformation of the urea motif engaged in extensive pi-interactions with the protein.

Binding Sites↗
PubMed1995

Second opinion: a computer expert system designed to aid in the determination of spectacle lens prescriptions.

BACKGROUND: Expert systems (ESs) are computer programs that simulate the decision-making ability of human experts. In this project, an ES was developed that used optometric data and decision rules to determine spectacle lens prescription powers. METHODS: Decision rules derived from clinical experience and standard references were provided to a commercially available shell program to create an ES called Second Opinion. The ES determined spherical, cylindrical, and add powers designed to provide maximum acuity consistent with a high probability of patient acceptance. CONCLUSIONS: Second Opinion demonstrates how a computer program can be used to analyze optometric data and offer suggestions regarding lens prescriptions.

Adult↗
PubMed2000

Molecular modeling and computer aided drug design. Examples of their applications in medicinal chemistry.

The development of new drugs with potential therapeutic applications is one of the most complex and difficult process in the pharmaceutical industry. Millions of dollars and man-hours are devoted to the discovery of new therapeutical agents. As, the activity of a drug is the result of a multitude of factors such as bioavailability, toxicity and metabolism, rational drug design has been utopias for centuries. Very recently, impressive technological advances in areas such as structural characterization of biomacromolecules, computer sciences and molecular biology have made rational drug design feasible. The aim of this review is to give an outline of studies in the field of medicinal chemistry in which molecular modeling has helped in the discovery process of new drugs. The emphasis will be on lead generation and optimization.

Computer-Aided Design↗
PubMed2001

Aspartic protease inhibitors designed from computer-generated templates bind as predicted.

[reaction: see text] Novel tripeptide-derived peptidomimetics 1, 7ab, and 8ab, inspired by templates generated by the structure-generating program GrowMol, were synthesized, shown to inhibit Rhizopus chinensis pepsin, and found by X-ray crystallography to bind to the enzyme in the GrowMol-predicted mode. Repetitive evaluation of the computer-generated templates for synthetic feasibility and optimal enzyme interactions led to the designed compounds.

Aspartic Acid Endopeptidases↗
PubMedDate not supplied

[Computer-assisted vaccine design].

With the modern molecular biology techniques, it has been possible to detect, isolate and clone biological macromolecules, which could be used as immunogenes in artificial vaccine constructs. In the post-genomic era, the prospective immunogenic components are searched using bionformatic tools and proteomic technologies. Today it is quite realistic to combine the artificial vaccine constructs from the preselected molecular components. Existing computational methods are able to detect the potential immunogenes in genomic sequences, predict their characteristics and subcellular location. The set of methods is designed to predict the T- and B-epitopes that can be used as components of minimal vaccine constructs. The variety of systems for production and delivery of vaccines are developed and tested. These include transgenic plants, bacterial and viral vectors, DNA molecules etc. Several informational resources provide free access to molecular immunology data and deliver services on prediction of antigenic features. Several artificial vaccines have already been launched, but much more preparations are under preclinical and clinical trials. Computer-aided design of vaccines may significantly decrease time and costs required for their development. Modern bioinformatic technologies are now employed for discovery of more effective and potent vaccine.

Animals↗
PubMed2005

Computer-based de novo design of drug-like molecules.

Ever since the first automated de novo design techniques were conceived only 15 years ago, the computer-based design of hit and lead structure candidates has emerged as a complementary approach to high-throughput screening. Although many challenges remain, de novo design supports drug discovery projects by generating novel pharmaceutically active agents with desired properties in a cost- and time-efficient manner. In this review, we outline the various design concepts and highlight current developments in computer-based de novo design.

Computer-Aided Design↗