Organic Chemistry in Drug Discovery-Reference-Cited by-同舟云学术

Organic Chemistry in Drug Discovery

Published:2004-03-19 Issue:5665 Volume:303 Page:1810-1813
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

MacCoss Malcolm¹²,Baillie Thomas A.¹²

Affiliation:

1. Department of Basic Chemistry, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.

2. Department of Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, West Point, PA 19486, USA.

Abstract

The role played by organic chemistry in the pharmaceutical industry continues to be one of the main drivers in the drug discovery process. However, the precise nature of that role is undergoing a visible change, not only because of the new synthetic methods and technologies now available to the synthetic and medicinal chemist, but also in several key areas, particularly in drug metabolism and chemical toxicology, as chemists deal with the ever more rapid turnaround of testing data that influences their day-to-day decisions.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference17 articles.

1. In this discussion a “hit” is defined as a nonoptimized structure obtained from some screening process on a target protein. It is often a very weak binder and is likely to have a nonoptimized pharmacokinetic profile. A “lead” is defined as a structure that has been derived from an early “hit” and although still not fully optimized has been shown to have some appropriate characteristics to be a precursor of a drug entity. Often a good lead will have shown some proof-of-concept activity in an in vivo pharmacological model but will likely not have been fully optimized for pharmacokinetic properties or undesirable off-target activities.

2. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

3. In the discovery setting the rule of five ( 2 ) predicts that poor absorption or permeation of drugs is more likely when a drug molecule possesses either (i) more than 5 hydrogen bond donors (ii) 10 hydrogen bond acceptors (iii) a molecular weight greater than 500 or (iv) a calculated logP greater than 5.

4. Screening for the potential of a drug candidate to cause idiosyncratic drug reactions

5. Drug−Protein Adducts: An Industry Perspective on Minimizing the Potential for Drug Bioactivation in Drug Discovery and Development

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