Molecular quantum similarity in QSAR: applications in computer-aided molecular design

La present tesi està centrada en l'ús de la Teoria de Semblança Quàntica per a calcular descriptors moleculars. Aquests descriptors s'utilitzen com a paràmetres estructurals per a derivar correlacions entre l'estructura i la funció o activitat experimental per a un conjunt de compostos. Els estudis de Relacions Quantitatives Estructura-Activitat són d'especial interès per al disseny racional de molècules assistit per ordinador i, en particular, per al disseny de fàrmacs. Aquesta memòria consta de quatre parts diferenciades. En els dos primers blocs es revisen els fonaments de la teoria de semblança quàntica, així com l'aproximació topològica basada en la teoria de grafs. Ambdues teories es fan servir per a calcular els descriptors moleculars. En el segon bloc, s'ha de remarcar la programació i implementació de programari per a calcular els anomenats índexs topològics de semblança quàntica. La tercera secció detalla les bases de les Relacions Quantitatives Estructura-Activitat i, finalment, el darrer apartat recull els resultats d'aplicació obtinguts per a diferents sistemes biològics.

Computer-Aided Drug Design of Pyranopyrazoles and Related Compounds for Checkpoint Kinase-1

Checkpoint-1 kinase plays an important role in the G(2)M cell cycle control, therefore its inhibition by small molecules is of great therapeutic interest in oncology. In this paper, we have reported the virtual screening of an in-house library of 2499 pyranopyrazole derivatives against the ATP-binding site of Chk1 kinase using Glide 5.0 program, which resulted in six hits. All these ligands were docked into the site forming most crucial interactions with Cys87, Glu91 and Leu15 residues. From the observed results these ligands are suggested to be potent inhibitors of Chk1 kinase with sufficient scope for further elaboration.

ISO 13567 - The Proposed International Standard for Structuring Layers in Computer Aided Building Design

Layering is a widely used method for structuring data in CAD-models. During the last few years national standardisation organisations, professional associations, user groups for particular CAD-systems, individual companies etc. have issued numerous standards and guidelines for the naming and structuring of layers in building design. In order to increase the integration of CAD data in the industry as a whole ISO recently decided to define an international standard for layer usage. The resulting standard proposal, ISO 13567, is a rather complex framework standard which strives to be more of a union than the least common denominator of the capabilities of existing guidelines. A number of principles have been followed in the design of the proposal. The first one is the separation of the conceptual organisation of information (semantics) from the way this information is coded (syntax). The second one is orthogonality - the fact that many ways of classifying information are independent of each other and can be applied in combinations. The third overriding principle is the reuse of existing national or international standards whenever appropriate. The fourth principle allows users to apply well-defined subsets of the overall superset of possible layernames. This article describes the semantic organisation of the standard proposal as well as its default syntax. Important information categories deal with the party responsible for the information, the type of building element shown, whether a layer contains the direct graphical description of a building part or additional information needed in an output drawing etc. Non-mandatory information categories facilitate the structuring of information in rebuilding projects, use of layers for spatial grouping in large multi-storey projects, and storing multiple representations intended for different drawing scales in the same model. Pilot testing of ISO 13567 is currently being carried out in a number of countries which have been involved in the definition of the standard. In the article two implementations, which have been carried out independently in Sweden and Finland, are described. The article concludes with a discussion of the benefits and possible drawbacks of the standard. Incremental development within the industry, (where ”best practice” can become ”common practice” via a standard such as ISO 13567), is contrasted with the more idealistic scenario of building product models. The relationship between CAD-layering, document management product modelling and building element classification is also discussed.

Functional device models and computer aided circuit design

Thesis (M.S.)--University of Illinois.

Computer aided geometric design of form-rolls for NC manufacture

Conventional methods of form-roll design and manufacture for Cold Roll-Forming of thin-walled metal sections have been entirely manual, time consuming and prone to errors, resulting in inefficiency and high production costs. With the use of computers, lead time can be significantly improved, particularly for those aspects involving routine but tedious human decisions and actions. This thesis describes the development of computer aided tools for producing form-roll designs for NC manufacture in the CAD/CAM environment. The work was undertaken to modernise the existing activity of a company manufacturing thin-walled sections. The investigated areas of the activity, including the design and drafting of the finished section, the flower patterns, the 10 to 1 templates, and the rolls complete with pinch-difference surfaces, side-rolls and extension-contours, have been successfully computerised by software development . Data generated by the developed software can be further processed for roll manufacturing using NC lathes. The software has been specially designed for portability to facilitate its implementation on different computers. The Opening-Radii method of forming was introduced as a subsitute to the conventional method for better forming. Most of the essential aspects in roll design have been successfully incorporated in the software. With computerisation, extensive standardisation in existing roll design practices and the use of more reliable and scientifically-based methods have been achieved. Satisfactory and beneficial results have also been obtained by the company in using the software through a terminal linked to the University by a GPO line. Both lead time and productivity in roll design and manufacture have been significantly improved. It is therefore concluded that computerisation in the design of form-rolls for automation by software development is viable. The work also demonstrated the promising nature of the CAD/CAM approach.

Implementation of placement and routing algorithms for computer aided design of printed circuit boards

The Printed Circuit Board (PCB) layout design is one of the most important and time consuming phases during equipment design process in all electronic industries. This paper is concerned with the development and implementation of a computer aided PCB design package. A set of programs which operate on a description of the circuit supplied by the user in the form of a data file and subsequently design the layout of a double-sided PCB has been developed. The algorithms used for the design of the PCB optimise the board area and the length of copper tracks used for the interconnections. The output of the package is the layout drawing of the PCB, drawn on a CALCOMP hard copy plotter and a Tektronix 4012 storage graphics display terminal. The routing density (the board area required for one component) achieved by this package is typically 0.8 sq. inch per IC. The package is implemented on a DEC 1090 system in Pascal and FORTRAN and SIGN(1) graphics package is used for display generation.

Validated ligand binding sites in CCK receptors. Next step: Computer aided design of novel CCK ligands

Computer-aided drug design becomes an important part of G-protein coupled receptors (GPCR) drug discovery process that is applied for improving the efficiency of derivation and optimization of novel ligands. It represents the combination of methods that-use-structural information of a receptor binding site of known ligands to design new ligands. In this report, we give a brief description of ligand binding sites in cholecystokinin and gastrin receptors (CK1R and CCK2R) which were delineated using experimental and computational methods, and then, we show how the validated ligand binding sites can be used to design and improve novel ligands. The translation of the knowledge of ligand-binding sites of different GPCRs to computer-aided design of novel ligands is summarized.

Structure- and ligand-based drug design approaches for neglected tropical diseases

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. Structure( SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.

Multi-objective optimization of the molecular structure of refrigerants

The aim of this work was to develop a new methodology, which can be used to design new refrigerants that are better than the currently used refrigerants. The methodology draws some parallels with the general approach of computer aided molecular design. However, the mathematical way of representing the molecular structure of an organic compound and the use of meta models during the optimization process make it different. In essence, this approach aimed to generate molecules that conform to various property requirements that are known and specified a priori. A modified way of mathematically representing the molecular structure of an organic compound having up to four carbon atoms, along with atoms of other elements such as hydrogen, oxygen, fluorine, chlorine and bromine, was developed. The normal boiling temperature, enthalpy of vaporization, vapor pressure, tropospheric lifetime and biodegradability of 295 different organic compounds, were collected from open literature and data bases or estimated. Surrogate models linking the previously mentioned quantities with the molecular structure were developed. Constraints ensuring the generation of structurally feasible molecules were formulated and used in commercially available optimization algorithms to generate molecular structures of promising new refrigerants. This study was intended to serve as a proof-of-concept of designing refrigerants using the newly developed methodology.

An in silico approach for screening flavonoids as P-glycoprotein inhibitors based on a Bayesian-regularized neural network

P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding cytotoxic agents out of cells, resulting in an obstacle in chemotherapeutic treatment of cancer. In order to aid in the development of potential P-gp inhibitors, we constructed a quantitative structure-activity relationship (QSAR) model of flavonoids as P-gp inhibitors based on Bayesian-regularized neural network (BRNN). A dataset of 57 flavonoids collected from a literature binding to the C-terminal nucleotide-binding domain of mouse P-gp was compiled. The predictive ability of the model was assessed using a test set that was independent of the training set, which showed a standard error of prediction of 0.146 +/- 0.006 (data scaled from 0 to 1). Meanwhile, two other mathematical tools, back-propagation neural network (BPNN) and partial least squares (PLS) were also attempted to build QSAR models. The BRNN provided slightly better results for the test set compared to BPNN, but the difference was not significant according to F-statistic at p = 0.05. The PLS failed to build a reliable model in the present study. Our study indicates that the BRNN-based in silico model has good potential in facilitating the prediction of P-gp flavonoid inhibitors and might be applied in further drug design.