a. web
members.tripod.com/stephanielau/tq/designdrug.htm
N.e.w D.r.u.g.s B.y D.e.s.i.g.n. Talk to anyone in the pharmaceutical industry, and you'll soon discover that genetics is the biggest thing to hit drug research since a penicillin mold floated into Alexander Fleming's pert dish. Sure, scientists have long known genes play a role in almost every ailment from Alzheimer's to yellow fever. But it is only in the past few years that they've learned how to use that information to identify a multitude of new targets and pathways for drug design.

www.phrma.org/genomics/
The Pharmaceutical Research and Manufacturers of America presents Genomics: A Global Resource. Includes news, lexicon, legislation, environment, therapeutics, issues, and bioinformatics. Under news are links to newspaper articles, news wires, NIH publications, press releases from science journals. From January '99 through today.

www.apnet.com/www/journal/ge.htm
Genomics journal online.

www.nih.gov/nigms/news/meetings/structural_genomics_targets.html
A summary of a conference held by the NIGMS on Structural Genomics Targets.

bioinfo.weizmann.ac.il/cards/
GeneCards: integrates information about human genes and diseases, the cellular functions of their products. Provides context-related links to outstanding Web sites, and ready-to-click search buttons for major Web resources. Features a guidance system that helps you to find information.

www3.ncbi.nlm.nih.gov/Omim/searchomim.html
OMIM (Online Mendelian Inheritance in Man): Extensive information about diseases and genes involved in them. With links to Medline references and more

bioinformatics.weizmann.ac.il/hotmolecbase/
HotMolecBase - Molecules for Medicine. A database of 'hot' proteins and other biologically active molecules (lipids, carbohydrates, and gases), their cell and molecular biology, involvement in diseases and medical applications. The database can be searched by disease or by molecule name. A list of entries and a search engine are available

www.hgsi.com/index.html
Human Genome Sciences is an emerging pharmaceutical company with the mission to predict, prevent, detect, treat and cure disease.

www.nifg.org/about.html
The Novartis Institute for Functional Genomics will become one of the largest facilities uniquely dedicated to utilizing the developing science of genomics to identify therapeutic research targets, with causal relationships to major diseases. (just about the institute)

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Bailey, David S., Alexander Bondar, L Mike Furness. 1998. Pharmacogenomics ­ it's not just pharmacogenetics [Review]. Current Opinion in Biotechnology. 9:595-601.
Abstract: New technologies in both combinatorial chemistry and combinatorial biology promise to unlock new opportunities for drug discovery and lead optimisation. Using such genome-based technologies to measure the dynamic properties of pharmacological systems, pharmacogenomics can now provide an objective measure of a drug's biological efficacy, including its potential adverse effects.
http://www.current-opinion.com/display.asp?file=subjects/jbio/main.htm

Whitcombe, David, Clive R Newton, Stephen Little. 1998. Advances in approaches to DNA-based diagnostics. [Review] Current Opinion in Biotechnology. 9:602-608.
Abstract: The most tangible advances in DNA diagnostics during the past year have been in enhancing existing techniques to simplify their use and improve throughput. This has led to simplified genotyping methods using homogeneous analysis coupled with spectral data output. Miniaturisation and increased throughput have also been achieved through improvements in DNA chip technology.
http://www.current-opinion.com/display.asp?file=subjects/jbio/main.htm

Watson, Andrew. Abhijit Mazumder, Michael Stewart, Sriram Balasubramanian. 1998. Technology for microarray analysis of gene expression. [Review] Current Opinion in Biotechnology. 9:609-614
Abstract: The past year has demonstrated the versatility of microarrays for the analysis of whole model-organism genomes and has seen the development of chips to measure the expression of 40,000 human genes. Microarray technology has also become considerably more robust and sensitive. Technology enhancements include the use of noncontact printing methods, improved 2-color sample preparation, and statistically based software for data analysis.
http://www.current-opinion.com/display.asp?file=subjects/jbio/main.htm

Saunders, Nigel J., E Richard Moxon. 1998. Implications of sequencing bacterial genomes for pathogenesis and vaccine development [Review] Current Opinion in Biotechnology. 9:618-623.
Abstract: Improvements in homology search methodology and functional predictions are being complemented by the increase in the volume of sequence data with which comparative analyses can be performed. The experimental methods needed for investigation of gene function and expression in a variety of model systems of infection continue to develop. The identification of surface-exposed microbial structures and their conservation in natural populations of pathogenic species offers prospects for developing novel vaccines. A major challenge is the development of efficient screening methods to select the most promising candidates, such as immunisation with DNA.
http://www.current-opinion.com/display.asp?file=subjects/jbio/main.htm

Erickson, John W. and Stanley K. Burt. 1996. Structural Mechanisms of HIV Drug Resistance.
Annual Review of Pharmacology and Toxicology, 36: 545-571,
Abstract: Antiviral therapy for AIDS has focused on the discovery and design of inhibitors for two main enzyme targets of the human immunodeficiency virus type 1 (HIV)--reverse transcriptase (RT) and protease (PR). Despite several classes of promising new anti-HIV agents, the clinical emergence of drug-resistant variants of HIV has severely limited the long-term effectiveness of these drugs. Genetic analysis of resistant virus has identified a number of critical mutations in the RT and PR genes. Structural analysis of inhibitor-enzyme complexes and mutational modeling studies are leading to a better understanding of how these drug-resistance mutations exert their effects at a structural level. These insights have implications for the design of new drugs and therapeutic strategies to combat drug resistance to AIDS.

Wlodawer, Alexander and Jiri Vondrasek. 1998. Inhibitors of HIV-1 Protease: A Major
Success of Structure-Assisted Drug Design Annu. Rev. Biophys. Biomol. Struct. 27:249-284.
Abstract: Retroviral protease (PR) from the human immunodeficiency virus type 1 (HIV-1) was identified over a decade ago as a potential target for structure-based drug design. This effort was very successful. Four drugs are already approved, and others are undergoing clinical trials. The techniques utilized in this remarkable example of structure-assisted drug design included crystallography, NMR, computational studies, and advanced chemical synthesis. The development of these drugs is discussed in detail. Other approaches to designing HIV-1 PR inhibitors, based on the concepts of symmetry and on the replacement of a water molecule that had been found tetrahedrally coordinated
between the enzyme and the inhibitors, are also discussed. The emergence of drug-induced mutations of HIV-1 PR leads to rapid loss of potency of the existing drugs and to the need to continue the development process. The structural basis of drug resistance and the ways of overcoming this phenomenon are mentioned.

Rosin, Christopher D., Richard K. Belew, Garrett M. Morris, Arthur J. Olson, and David S.
Goodsell. 1999. Coevolutionary analysis of resistance-evading peptidomimetic inhibitors
of HIV-1 protease. PNAS. 96(4): 1369-1374.
Abstract: We have developed a coevolutionary method for the computational design of HIV-1 protease inhibitors selected for their ability to retain efficacy in the face of protease mutation. For HIV-1 protease, typical drug design techniques are shown to be ineffective for the design of resistance-evading inhibitors: An inhibitor that is a direct analogue of one of the natural substrates will be susceptible to resistance mutation, as will inhibitors designed to fill the active site of the wild-type or a mutant enzyme. Two design principles are demonstrated: (i) For enzymes with broad substrate specificity, such as HIV-1 protease, resistance-evading inhibitors are best designed against the immutable properties of the active site the properties that must be conserved in any mutant protease to retain the ability to bind and cleave all of the native substrates. (ii) Robust resistance-evading inhibitors can be designed by optimizing activity simultaneously against a large set of mutant enzymes, incorporating as much of the mutational space as possible.

Hardy, Larry W.; Janet S. Finer-Moore; William R. Montfort; Melvin O. Jones; Daniel V. Santi;
Robert M. Stroud. 1987. Atomic structure of thymidylate synthase: target for rational drug design. Science.235:448

Enzyme structure to help drug design. (thymidylate synthetase). Science News, Feb 7, 1987
131:88

Weiss, Rick. 1987. New class of antibiotics confirmed. (rational drug design) Science News.
132:180

Kuntz, Irwin D. 1992. Structure-based strategies for drug design and discovery. Science.
257(5073):1078
Abstract: Most drugs have been discovered in random screens or by exploiting information about macromolecular receptors. One source of this information is in the structures of critical proteins and nucleic acids. The structure-based approach to design
couples this information with specialized computer programs to propose novel
enzyme inhibitors and other therapeutic agents. Iterated design cycles have
produced compounds now in clinical trials. The combination of molecular structure
determination and computation is emerging as an important tool for drug
development. These ideas will be applied to acquired immunodeficiency syndrome
(AIDS) and bacterial drug resistance.

Brugge, Joan S. 1993. New intracellular targets for therapeutic drug design. Science.
260(5110):912
Abstract: Greater understanding of cellular biology has led to new techniques for
developing therapeutic drugs. Instead of testing naturally occurring compounds for pharmacological effect, researchers can use the understanding of cellular signaling mechanisms to design drug molecule structures that can modify or inhibit such mechanisms.

Cohen, Fred E. 1993. Nucleic Acid Targeted Drug Design. (book reviews) Science. 261(5122):
773

Bugg, Charles E. William M. Carson; John A. Montgomery. 1993. Drugs by design. Scientific
American. 269(6): 92
Abstract: Structure-based drug design, which involves the chemical synthesis of therapeutics based on the molecules with which they will react in the body, is now seen as a viable alternative to trial-and-error drug discovery. The effort to design an inhibitor to purine nucleoside phosphorylase (PNP) is described.

Service, Robert F. 1996. Combinatorial chemistry hits the drug market. Science. 272(5266):
1266
Abstract: Used to simultaneously to create and test new compounds, combinatorialchemistry is gaining popularity among pharmaceutical companies as new techniques are developed to boost the method's effectiveness and efficiency.

Hajduk, Philip J.; Robert P. Meadows; Stephen W. Fesik. 1997. Discovering high-affinity
ligands for proteins: drug design.Science. 278(5337):497
Abstract: Methods of identifying highly bondable molecules, for new drug
synthesis, are examined. The goal is to find linked compounds with submicromolar affininties, using combinational chemistry and parallel synthesis.

New drugs target HIV's deep pocket. .Antiviral Weekly, Oct 11, 1999 p4

Novitt-Moreno, Anne. 1998. AIDS Will the Future Bring a Cure? Current Health 2. 25(4):6
Abstract: HIV drugs have had some success in reducing the number of deaths
associated with AIDS. However, researchers revealed at the 12th World AIDS
Conference in Geneva, Switzerland, that the HIV virus has learned to resist the drug therapies. Protease inhibitors were thought to be a way to treat the disease as a chronic disease as opposed to a fatal one. The protease inhibitors also caused abnormal fat deposits and high blood sugar levels.

Cohen, Jon. 1996. Protease inhibitors: a tale of two companies. (Merck and Abbott
Laboratories). Science. 272(5270):1882
Abstract: Merck and Abbott developed the protease inhibitors ritonavir and
indinavir that when used with other anti-HIV drugs can reduce the amount of HIV in most infected people to levels that are not even detectable. The companies' different corporate, scientific and political strategies are examined.

Cowley, Geoffrey. 1996. Living longer with HIV. Newsweek. 127(7):60
Abstract: A new class of drugs called protease inhibitors hold promise of keeping HIV from developing into AIDS. AZT and similar drugs keep HIV from integrating into host cells, but the new agents, saquinavir, indinavir and ritonavir, keep HIV from reproducing after it eventually gets by the AZT.

Fackelmann, Kathy A. 1994. Reverse logic: smart drugs target HIV and a herpesvirus.
Science News. 146(6):88
Abstract: Antisense compounds prevent messenger RNA from providing
instructions to the cell about how to manufacture a disease-causing protein.
Research on antisense compounds designed to fight HIV and cytomegalovirus is discussed.

Broder, Samuel; Hiroaki Mitsuya; Robert Yarchoan. 1990. Molecular targets for AIDS therapy.
Science. 249(4976): 1533
Abstract: The development of antiretroviral therapy against acquired immunodeficiency syndrome (AIDS) has been an intense research effort since the discovery of the causative agent, human immunodeficiency virus (HIV). A large array of drugs and biologic substances can inhibit HIV replication in vitro. Nucleoside analogs - particularly those belonging to the dideoxynucleoside family - can inhibit reverse transcriptase after anabolic phosphorylation. 3'-Azido-2',3'-dideoxythymidine (AZT) was the first such drug tested in individuals with AIDS, and considerable knowledge of structure-activity relations has emerged for this class of drugs. However, virtually every step in the replication of HIV could serve as a target for a new therapeutic intervention. In the future, non-nucleoside-type drugs will likely become more important in the experimental therapy of AIDS, and antiretroviral therapy will exert major effects against the morbidity and mortality caused by HIV.

Palca, Joseph. 1990. Shooting at a new HIV target. Science. 247(4941): 410
Abstract: Two teams of researchers, one at Smith Kline and French Laboratories, the other at Upjohn Company, have discovered compounds which prevent the AIDS virus, HIV, from reproducing itself. The compounds work by interfering with a protein-degrading enzyme which the virus requires to reproduce. This enzyme, called an aspartic proteinase, resembles the human enzyme renin, which gave researchers a head start in understanding its structure and function and in developing compounds to block it. In tissue culture, HIV-infected cells continue to produce virus in the presence of the enzyme inhibitors, but the new virus is incapable of reproduction. The enzyme inhibitors have not yet been tested in patients; the step to patients is a large one. Proteinases are common in the body, and if it turns out that
the HIV-protease inhibitor also inhibits an enzyme required for normal body
processes, the treatment might be as bad as the disease. Researchers point out that even though taking a tissue culture phenomenon and turning it into a drug is a difficult step to take, it is a necessary one in the development of new anti-HIV drugs.

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Sneader, Walter. Drug prototypes and their exploitation. Chichester ; New York : Wiley, c1996.
(SC/Science )

Korolkovas, Andrejus. Essentials of molecular pharmacology: background for drug design New York, Wiley-Interscience, 1970 (MH/Main )

Glaxo Wellcome. Intelligent drug design. London : Macmillan Magazines, 1996 (AC/Science )

Martin, Yvonne Connolly, Martin, Eberhard Kutter, Volkhard Austel, eds. Modern drug research : paths to better and safer drugs. New York : Dekker, c1989 (SC/Science)

Dean, P.M., G. Jolles, and C.G. Newton, eds. New perspectives in drug design based on Rhône-Poulenc Rorer Round Table Conference (9th : 1994 : Turnberry, Scotland) San Diego : Academic Press, c1995 (1 copy ordered for SC/Science on 04-02-98)

Cleland, Jeffrey L. and Charles S. Craik, eds. Protein engineering : principles and practice.
New York : Wiley-Liss, c1996(SC/Science )

Smith, H. John, ed. Smith and Williams' introduction to the principles of drug design and action.
Australia : Harwood Academic Publishers, c1998. 3rd ed. (SC/Science)

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