Tetrahedron Computer Methodology最新文献

The design of non-peptidic inhibitors of the human immunodeficiency virus type 1 (HIV-1) protease as potential therapeutic agents against AIDS has been the subject of intense research. Recently, the X-ray crystal structures of several HIV-1 protease/inhibitor complexes have been solved, including one that contains a C₂ symmetric inhibitor, A-74704. In this report, three-dimensional substructure searching, using the program ALADDIN, was used to identify novel, non-peptidic inhibitors of HIV-1 protease. Three-dimensional substructures, or patterns of atoms related by specific geometric constraints, were constructed based on an evaluation of the detailed interactions between A-74704 and the active site of the protease. The substructures included a functional replacement for the buried water molecule observed in the inhibitor/protease complex. Search targets based on these substructures were used to query several large databases of three-dimensional structures to identify small molecule structures with the potential to inhibit HIV-1 protease. Approximately thirty compounds were selected from those found in the searches and tested for HIV-1 protease inhibition. Three structurally-related non-peptidic compounds displayed inhibition in the 10 to 100 μM range. The identification of these compounds may represent an advance towards the de novo design of non-peptidic inhibitors of HIV-1 protease.

A system is being developed, based on structure generation methods, for the design of molecules to fit a variety of constraints. The system is modular and uses techniques from artificial intelligence to solve general problems in molecule design. Heuristics are being developed based, in part, on the different kinds of constraints that might be available to the system, e.g., the shape and electrostatic nature of a cavity. The heuristics are then used to restrict the combinatorial explosion that is inherent in structure generation. The program has been tested using the appa binding site of Trypsin and a range of different structures that fit the site have been generated. Some of these structures are very closely related to appa and the predictive value of the program has also been demonstrated.

Conversion of the Cambridge Structural Database to compatible 3D Daylight Thor and maccs-3d databases has been accomplished with approximately 75% of the entries with fractional coordinates being successfully converted. This was achieved by novel use of the Daylight Chemical Information Systems, Inc. software package in order to integrate both the chemical and the crystallographic connectivities into a unique smiles representation complete with full hydrogen specification. Fractional crystallographic coordinates were converted to Daylight tdt (Thor datatree) files utilizing a modified version of InterCon (QCPE 598). The unique smiles, coupled with both 2D and 3D cartesian coordinates, as well as information from the corresponding bibliographic file, formed the basis of the Thor database. The unique smiles (with coordinates) is easily converted into either a maccs-ii or maccs-3d suitable molfile.

QS-Edit 1.0 is a query structure editor created for the Macintosh computer that provides a graphical front end to the CAS Online Registry and Beilstein databases. A query structure drawn with this program is converted to the commands needed by the CAS Online computer to interpret the query. The program has been designed to be used most conveniently with Multifinder and a terminal program. The executable program is included on disk.

This paper shows the advantages of using chemometric strategies in QSAR of NKA analogues containing D-Tryptophan and behaving as highly selective NK-2 receptor antagonists: a) detecting the sequence with optimal antagonist activity, and b) having a strategy for selecting a few most informative sequences. The data set is included on disk as RVD .DAT.

A new way to formalize the description of [3,3]-sigmatropic rearrangement in annulenes is suggested. The straightforward procedure to search for bullvalene-like annulenes is described in terms of graph theory. The transformation of a chemical graph to its homomorphic image allows description of the Cope rearrangement as a redistribution of labels on the edges of a homomorphic graph. Two selection criteria are suggested for evaluation of the topological possibility of degenerate Cope rearrangements, which are followed by equalization of carbon and hydrogen atoms. The results of the exhaustive search for the bullvalene-like structures among the planar annulenes are presented and discussed, as well as for 6–18 vertex homomorphic images of non-planar annulene structures. The results of a brute-force attempt to find the analogy of bullvalene among the C_n (n=6,8) families are also briefly described.

The program MMOL reads MacroModel formatted structure files and converts them into MDL's MolFile format. The program is included on disk.