Molecular Modeling in the Discovery of Drug Leads

@article{Milne1996MolecularMI,
  title={Molecular Modeling in the Discovery of Drug Leads},
  author={George W. A. Milne and Shaomeng Wang and Marc C. Nicklaus},
  journal={Journal of chemical information and computer sciences},
  year={1996},
  volume={36 4},
  pages={
          726-30
        }
}
The National Cancer Institute of the U.S.A. maintains a repository of about 500,000 chemicals which it has tested at some time for anticancer activity. As new chemotherapeutic targets present themselves, methods have been developed by which this large database can be re-examined without resorting to expensive high-volume biological screening. Electronic screening, the method described in this paper, begins with the identification of a target enzyme. The pharmacophore used by the enzyme in… 
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12 Citations

12 Citations

Citation Type

Citation Type

A Systemsatic Approach to Finding New Lead Structures Having Biological Activity
TLDR
It was shown that one of these new structure representations is suitable for treating problems in combinatorial synthesis, and implementation of these procedures on highly parallel computers has proved that datasets of several hundreds of thousands of structures can be treated with acceptable computation times.
Pharmacophores in drug design and discovery.
TLDR
The ways in which pharmacophores can be found and characterized and the details of the 3D searching methods are described, which allows the retrieval of all compounds possessing a specified set of atoms with a given 3D geometry.
Potent inhibitors of human immunodeficiency virus type 1 integrase: identification of a novel four-point pharmacophore and tetracyclines as novel inhibitors.
TLDR
Remarkable potency against the IN in the absence of divalent metals and the core enzyme coupled with water solubility makes tetracyclines potential candidates for X-ray crystal structure determination with IN.
Drug discovery: past, present and future.
  • P. N. Kaul
  • Biology
    Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques
  • 1998
TLDR
As the authors understand more about the co-ordinating and regulating powers of the cerebral cortex during the next century, man may be able to use bio-feedback training to voluntarily regulate the release of neurotransmitters, hormones, and other molecules involved in the regulation of various physiological processes in health as well as in disease.
Prediction of aqueous solubility for a diverse set of organic compounds based on atom-type electrotopological state indices.
Estimation of Aqueous Solubility for a Diverse Set of Organic Compounds Based on Molecular Topology
An accurate and generally applicable method for estimating aqueous solubilities for a diverse set of 1297 organic compounds based on multilinear regression and artificial neural network modeling was…
Estimation of Aqueous Solubility for a Diverse Set of Organic Compounds Based on Molecular Topology.
An accurate and generally applicable method for estimating aqueous solubilities for a diverse set of 1297 organic compounds based on multilinear regression and artificial neural network modeling was…
Protein–ligand docking and structure-based drug design
TLDR
Current methods and their applications are reviewed, some recent successes in structure-based drug design are highlighted, and scoring functions and docking search procedures are highlighted.
From Chemical Graphs to 3D Molecular Modeling
Constitutional isomerism is defined as that type of isomerism (i.e., different structures corresponding to the same molecular formula) resulting from differences in vicinity relationships between…
The crystal structures of CeSiO4 and Ca2Ce8(SiO4)6O2
Two new solubility-limiting phases relevant to nuclear waste disposal are reported, namely CeSiO4 and Ca2Ce8(SiO4)O2, produced by hydrothermal synthesis at 180 °C. X-ray diffraction data are…
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References

SHOWING 1-10 OF 12 REFERENCES
Analysis of the phorbol ester pharmacophore on protein kinase C as a guide to the rational design of new classes of analogs.
TLDR
Members of a new and simplified class of activators were synthesized that possess the predicted essential structural features and inhibited specific phorbol ester binding to protein kinase C, albeit with low affinity (10-60 microM).
SPROUT: Recent developments in the de novo design of molecules
SPROUT is a computer program for constrained structure generation. It is designed to generate molecules for a range of applications in molecular recognition. The program uses a number of…
Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution.
TLDR
Amine (Nle, norleucine) with chemically synthesized HIV-1 (human immunodeficiency virus 1) protease was determined at 2.3 A resolution, and the protein molecule underwent substantial changes, particularly in an extended region corresponding to the "flaps" of the molecule.
Estimation of aqueous solubility of organic molecules by the group contribution approach. Application to the study of biodegradation
TLDR
It was found that although the water solubility was not the sole factor controlling the rate of biodegradation, ring compounds with greater solubilities were more likely to biodegrade at a faster rate.
Pharmacophoric pattern matching in files of 3d chemical structures: evaluation of search performance
The NCI Drug Information System. 2. DIS pre-registry
The Pre-Registry Module of the Drug Information System (DIS) is a staging area through which all new compounds are passed prior to acquisition and testing. Several methods are available for the entry…
Chem-X and CAMBRIDGE. Comparison of computer generated chemical structures with x-ray crystallographic data
TLDR
In the group of molecules examined, ChemModel produced structures that were essentially identical to those based upon X-ray data in 57% of the cases, compared with the corresponding figure for the widely used alternative model builder, CONCORD.
Solution structure of a cysteine rich domain of rat protein kinase C
TLDR
It is revealed that CRD2 adopts a globular fold allowing two non-consecutive sets of zinc-binding residues to form two separate metal-binding sites and allows insight into the molecular topology of a family of homologous proteins.
A small single-"finger" peptide from the erythroid transcription factor GATA-1 binds specifically to DNA as a zinc or iron complex.
TLDR
The results make it clear that the GATA-1 metal binding motif is quite distinct from that found in the steroid hormone family and that GATA -1 is a member of a separate class of DNA binding proteins.
Structural basis for misaminoacylation by mutant E. coli glutaminyl-tRNA synthetase enzymes.
TLDR
These genetic experiments define two positions in GlnRS where amino acid substitution results in a relaxed specificity of tRNA discrimination, and identify specific areas in the structure of theGlnRS:tRNA(Gln) complex that are critical to accurate t RNA discrimination by Gln RS.
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