Structure generation by reduction: a new strategy for computer-assisted structure elucidation

A problem common to computer programs for structure elucidation is the efficient and prospective use of the input information to constrain the structure generation process. The input may consist of potentially overlapping substructure requirements and alternative substructure interpretations of spectral data. Other useful information may be structural features that must not be present in the output structures. All of these may interact in a complex manner that is impossible to determine by use of a bond-by-bond structure assembly algorithm. A new method is described called structure reduction. In contrast to structure assembly, this method begins with a set of all bonds and removes inconsistent bonds as structure generation progresses. This results in a more efficient use of the input information and the ability to use potentially overlapping required substructures. Several examples illustrate the application of our computer program COCOA, which uses this method to solve real-world structure elucidation problems.     

SPROUT: A program for structure generation

Summary SPROUT is a new computer program for constrained structure generation that is designed to generate molecules for a range of applications in molecular recognition. It uses artificial intelligence techniques to moderate the combinatorial explosion that is inherent in structure generation. The program is presented here for the design of enzyme inhibitors. Structure generation is divided into two phases: (i) primary structure generation to produce molecular graphs to fit the steric constraints; and (ii) secondary structure generation which is the process of introducing appropriate functionality to the graphs to produce molecules that satisfy the secondary constraints, e.g., electrostatics and hydrophobicity. Primary structure generation has been tested on two enzyme receptor sites; the p-amidino-phenyl-pyruvate binding site of trypsin and the acetyl pepstatin binding site of HIV-1 protease. The program successfully generates structures that resemble known substrates and, more importantly, the predictive power of the program has been demonstrated by its ability to suggest novel structures.     

Organic Synthesis in the Age of Computers

The computer affords four areas of interest to synthetic chemists: (1) storage and retrieval of information; (2) complex calculations of shape and reaction dynamics; (3) artificial intelligence (AI) to solve synthetic and analytical problems; (4) overall direction of multiple laboratory experiments. Our work began 30 years ago initiating molecular geometry calculations to match experimental results. The explosive growth of computer power since will be illustrated. Synthesis design (as AI) requires an efficient protocol to search huge trees. The SYNGEN program is based on simplification and systematization, first of skeletal dissection, then of structure and reaction characterization, for generation of optimal synthesis routes. The program will be be described and its future development outlined. Finally, a perspective on the future of all four areas will be sketched, noting the necessary attendant growth in systematic use by chemists and in sympathetic interfaces by software designers.     

A program generator for describing copolymerization and network formation in step reactions

A multi-purpose computer program has been developed for describing copolymerization and network formation in step reactions. It operates at two hierarchical levels: a generation level and an application level. At the generation level, the class of problems is defined and prepared, and this information is used to generate automatically a problem-specific program based on generalized concepts of the branching theory. At the application level, the problem-specific program can be used for model calculations with all possible variations in recipes and kinetic parameters within the boundaries of the specific class of processes concerned.     

The direct configuration interaction method for general multireference expansions: Symmetric group approach

A computer implementation of the direct configuration interaction method formulated within the symmetric group approach is discussed. The formulation allows for an open-shell as well as for a multiconfigurational reference state. The number of all necessary formulas, derived by a computer for each integral type rather than for the individual integrals, is lower than in the currently existing techniques, including the unitary group approach. The logical structure of a general program for singly and doubly excited configurations is outlined. The efficiency of the symmetric group approach is demonstrated on a recently developed program, restricted to one reference state only.     

Application of artificial intelligence for chemical inference. XXV. A computer program for automated empirical 13C NMR rule formation

A computer program which generates empirical rules associating ¹³C NMR shifts with local structural environments is described. The program uses a heuristic method to search for common structural features for those carbon atoms exhibiting similar shifts. Rules have been generated by our program from a combined set of acyclic amine and paraffin data. Examples of these rules are presented, and their performance as a tool for structure elucidation is examined.     

AMBER: Assisted model building with energy refinement. A general program for modeling molecules and their interactions

We describe a computer program we have been developing to build models of molecules and calculate their interactions using empirical energy approaches. The program is sufficiently flexible and general to allow modeling of small molecules, as well as polymers. As an illustration, we present applications of the program to study the conformation of actinomycin D. In particular, we study the rotational isomerism about the D -Val-, L -Pro, and L -Pro-Sar amide bonds as well as comparing the energy and structure of the Sobell model and the x-ray structure of actinomycin D.     

Kekulé structure counts in coronoid hydrocarbons: A general solution

The Kekulé structure count (K) of a planar graph (in the graph-theoretical sense) is obtainable as the Pfaffian of a skew-symmetric adjacency matrix. This principle was used to design a general computer program for theK numbers of coronoid systems. Thus it became possible for the first time to determineK, as a matter of routine, during the computer-aided generation and enumeration of all types of Kekuléan coronoids, including those where perimeters of [4k] cycles are present. The methods are exemplified by a complete account (with figures andK numbers] of the 27 half essentially disconnected coronoids with the phenalene hole and 11 or 12 hexagons.     

Computer program for finding all possible cycles in graphs

A new approach is presented for identifying all possible cycles in graphs. Input data are the total numbers of vertices and edges, as well as the vertex adjacencies using arbitrary vertex numbering. A homeomorphically reduced graph (HRG) is constructed by ignoring vertices of degree less than three. The algorithm is based on successive generation of possible edge-combinations in the HRG. If a combination yields a cycle, it is either printed or stored and then finally printed in a list of all possible cycles arranged in the order of increasing ring size. A unique numbering of the cycle is used. The computer program is listed and exemplified. Computing times are given.     

On finding nonisomorphic connected subgraphs and distinct molecular substructures

The problem of finding all nonisomorphic subgraphs of a given graph (all distinct substructures of a given molecular structure) is discussed. A computer program is introduced that first generates all connected subgraphs and then uses a combination of well-discriminating graph invariants to eliminate duplicates. The program is broadly applicable, in particular for molecular graphs which may or may not contain unsaturation or heteroatoms. The number of distinct substructures (Ns), proposed earlier as a measure of a compound's complexity which takes into account its symmetry, is thus automatically obtained. As was to be expected, due to the nature of the problem the computational effort increases exponentially with problem size, whence in most cases complexity measures other than Ns are to be preferred.     

Computer supported structure elucidation of polymethoxy- and polyacetoxyxanthones. V—13C NMR spectroscopy of substituted xanthones

A procedure for developing ¹³C NMR chemical shift additivity rules for all 136 polymethoxyxanthones and all 136 polyacetoxyxanthones, based on multiple linear regression analysis, is reported. The influence of steric interactions between the substituents on the chemical shifts of the carbon atoms in the xanthone ring system is discussed and included in the calculations of the additivity rules for the polymethoxyxanthones. The derived chemical shift increments are implemented into the computer program SEOX 1. The extended program, SEOX 2, allows an automated structure elucidation of polyhydroxy-, polymethoxy- and polyacet-oxyxanthones. The increments are tested using the leave-one-out method in conjunction with SEOX 2, and have been found to be very suitable for this purpose.     

Manual construction and mathematics- and computer-aided counting of stereoisomers. The example of oligoinositols

Two methods to obtain numbers of stereoisomers and of achiral stereoisomers of a given molecular structure are detailed on the example of di- and triinositols. The first method is manual exhaustive construction free of redundance of all stereoisomers, which is rendered feasible by symmetry considerations despite the large number of isomeric triinositols (82176). The second method is counting without constructing, made possible by use of a mathematical tool, the Cauchy-Frobenius lemma, which actually is a formalized manner of considering symmetry. The results are compared to those obtained by computer-aided stereoisomer generation using the program MOLGEN 3.5. It is demonstrated that in their results all three methods agree.     

The NCI Drug Information System. 1. System overview

An interactive computer system has been designed to handle all the data associated with the National Cancer Institute's (NCI) drug screening program. The system resides on the NIH DEC System 10 computers and allows interactive access to the entire NCI screening data system. This contains over 20 separate databases, including a chemistry file of about 400,000 structures and a biology file of approximately 1.5 million test records. New compounds and test data are added daily to the files, and the system also controls and records all the daily operations of the screening program, such as acquisition, shipping, and biological testing of chemicals.     

CAPA--Computer Aided Pesticide Analysis. Computer program for the automated evaluation of chromatographic data for residue analysis of foods

Pesticide residue analysis in food by means of gas chromatography with columns of different polarity and several selective detectors provides the analyst with a great number of chromatographic data. The introduction of personal computer based chromatographic data systems into research laboratories increased the efficiency of information management and organization; user designed software packages now have direct access to the stored data. The computer program CAPA (Computer Aided Pesticide Analysis) was developed for the interpretation and evaluation of chromatographic results. The program is written in TURBO PASCAL 3.0 and consists of several subprograms. In the main database all pesticides are filed in a multidimensional structure. The various subprograms have access to this catalog of retention and response data. Using the subprogram INTERPRET, which is the core of CAPA, the analyst is provided with all information necessary to interpret a gas chromatogram: identification of calibrated pesticides and estimation of their concentration. Automated screening analyses can be evaluated with the subprogram AUTOINTERPRET, an automated of INTERPRET that uses all relevant information stored in the data base. A report is produced containing the pesticides found in the sample and proposals how to confirm them best with the equipment and methods available. Finally the analyst has to make the decision about the probable presence and quantity of the indicated pesticides and to project the next confirmatory step by using INTERPRET.     

High speed electrophoresis simulation for optimization of continuous flow electrophoresis and high performance capillary techniques: Part I. Computer model.

A computer program for high-speed simulation and optimization of electrophoretic processes has been developed for carrier-free systems of all kinds. The calculations are based on the one-dimensional dynamic (transient-state) model. The three-dimensional geometry of the simulation space can be chosen deliberately. With a highly efficient transport algorithm instead of complicated integration schemes for the transport equations, the calculation time can be effectively spent on various important parameters such as ionic strength, temperature, Joule heat, activity coefficients and concentration changes due to membranes. The parameter set of any carrier free electrophoretic method (i.e., continuous-flow electrophoresis, capillary isotachophoresis and high performance capillary zone electrophoresis) can be imported directly into the computer program by means of a graphic user interface. The program performs overnight-simulation of any electrophoretic system containing up to 15 components.     

Erfahrungen mit vier Softwarepaketen für Kinetische Auswertungen in der Thermischen Analyse

Four computer programs as well as one demo-version for non-linear evaluation of kinetic data in thermal analysis and calorimetry, were presented. The multi-task program TA-kin meets all mathematical requirements for solving the numerical assignments. It is shown that the so-called compensation effect is due to the mathematical structure of the Arrhenius equation. Several applications of TA-kin to a lot of DSC- and TG-measurements and isoperibolic batch experiments as well as adiabatic semi batch experiments realized by precision calorimetry have been discussed.     

quiral: a computer program for the synthesis of chiral molecules from sugars

The quiral computer program analyzes the 3D structure of a target organic molecule to find which sugar(s) can be used as a starting material for its synthesis. The program also proposes schemes for the preparation of rare or unavailable sugars whose chiral centers fit with those of the target molecule. Castanospermine, an anti-HIV natural compound is chosen as an example to illustrate what the quiral program achieves.     

Computer-assisted structure elucidation

Summary Program CASE, an evolving computer model of the structure elucidation process, treats three major tasks: reduction of the chemical and spectral properties of a compound of unknown structure to their structural implications, generation of all complete molecular structures compatible with the structural features identified, and ranking these structures on the basis of the degree of fit between predicted and observed spectral properties. The current program status is described and program application is illustrated.

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Strukturaufklärung mit Computer-Hilfe

Zusammenfassung Ein in Entwicklung befindliches Computer-Modell (program CASE) wird beschrieben, das hauptsächlich folgende drei Aufgaben erfüllt: Zuordnung der chemischen und spektralen Eigenschaften einer Verbindung unbekannter Struktur zu ihren strukturellen Bedeutungen; Aufstellung aller Strukturen, die mit den gefundenen Eigenschaften im Einklang stehen; Einordnung dieser Strukturen je nach Übereinstimmung mit den vorhergesagten und gefundenen Parametern. Der derzeitige Entwicklungsstand des Programms wird erläutert und die Anwendung diskutiert.

     

Exploring the limits of graph invariant- and spectrum-based discrimination of (sub)structures

The limits of a recently proposed computer method for finding all distinct substructures of a chemical structure are systematically explored within comprehensive graph samples which serve as supersets of the graphs corresponding to saturated hydrocarbons, both acyclic (up to n = 20) and (poly)cyclic (up to n = 10). Several pairs of smallest graphs and compounds are identified that cannot be distinguished using selected combinations of invariants such as combinations of Balaban's index J and graph matrix eigenvalues. As the most important result, it can now be stated that the computer program NIMSG, using J and distance eigenvalues, is safe within the domain of mono- through tetracyclic saturated hydrocarbon substructures up to n = 10 (oligocyclic decanes) and of all acyclic alkane substructures up to n = 19 (nonadecanes), i.e., it will not miss any of these substructures. For the regions surrounding this safe domain, upper limits are found for the numbers of substructures that may be lost in the worst case, and these are low. This taken together means that the computer program can be reasonably employed in chemistry whenever one is interested in finding the saturated hydrocarbon substructures. As to unsaturated and heteroatom containing substructures, there are reasons to conjecture that the method's resolving power for them is similar.     

Combinatorial models and algorithms in chemistry. Search for isomorphisms and automorphisms of molecular graphs

An algorithm for the recognition of all isomorphisms for any pair of labeled graphs as well as for generation of the graph group is described. Some results obtained with computer realization of the suggested algorithm are briefly discussed.