Current Topics in Medicinal Chemistry, Volume 4, No. 6, 2004
Contents
Hit-to-Lead: Driving Forces for the
Medicinal Chemist
Guest Editor: Benoit Deprez
and Rebecca Deprez-Poulain
Facts, Figures
and Trends in Lead Generation
Pp. 569-580
Rebecca Deprez-Poulain and
Benoit Deprez
The Design of
Screening Libraries Targeted at G-Protein Coupled Receptors Pp. 581-588
Roger Crossley
Molecular
Similarity and Property Similarity Pp. 589-600
Frederique Barbosa and Dragos Horvath
“It’s The
Chemistry, Stupid !”, or: The Impact of Early
Discovery Patent Applications on the Drug Development Process Pp. 601-608
Frank Landolt
Nicotinic
Acetylcholine Receptors: Ligand Design Issues
Guest
Editor: Jeffrey D. Schmitt
Recent
Developments in the Synthesis of Nicotinic Acetylcholine Receptor Ligands
Pp. 609-629
Scott R. Breining
Musings on a4b2
Nicotinic Acetylcholine (nACh) Receptor Pharmacophore Models Pp. 631-644
Richard A. Glennon, Malgorzata Dukat, Liang Liao
Rational Understanding of Nicotinic Receptors Drug Binding Pp. 645-651
Thomas Grutter, Nicolas Le Novere and Jean-Pierre Changeux
Abstracts
[Back to top] Facts,
Figures and Trends in Lead Generation
Rebecca Deprez-Poulain and
Benoit Deprez
The goal of this paper is to review the variety of approaches adopted to improve lead generation, and make the process easier for the chemist, faster and more likely to succeed in later phases of drug development. Our analysis shows that successful lead generation requires not only an accurate definition of the needs (to define the most relevant assay protocols and readouts), but most of all a good hit as a starting point. It also appears that teams where techniques are combined are more successful in that difficult game.
[Back to top] The Design of
Screening Libraries Targeted at G-Protein Coupled Receptors
Roger Crossley
The screening of large libraries in order to obtain hits for receptors of interest has been the mainstay of drug research for some time now. It is increasingly being recognised that this is a relatively inefficient way to achieve this end and the screening of libraries either designed or selected to hit particular targets is rapidly becoming the method of choice. The advantages in terms of success rate to achieve viable lead series are magnified by the cost and time savings achieved by screening more carefully selected groups of compounds.
A number of approaches have been used for the design and production of such libraries or methods for selection of such focused sets from larger diverse collections. These range from combinatorially produced ligand-mimetic approaches through pharmacophore-based design to those methods based on statistical selection techniques.Most recently, progress in chemogenomic approaches has thrown new light on the relationship between receptor sequence and compounds that interact at particular receptors and this is also having an impact on the design of targeted libraries.
[Back to top] Molecular
Similarity and Property Similarity
Frederique Barbosa and Dragos Horvath
This paper reviews the main efforts undertaken up to date in order to understand, rationalize and apply the similarity principle (similar compounds => similar properties) as a computational tool in modern drug discovery. The best suited mathematical expression of this classical working hypothesis of medicinal chemistry needs to be carefully chosen (out of the virtually infinite possible implementations in terms of molecular descriptors and molecular similarity metrics), in order to achieve an optimal validation of the hypothesis that molecules that are neighbors in the Structural Space will also display similar properties. This overview will show why no single “absolute” measure of molecular similarity can be conceived, and why molecular similarity scores should be considered tunable tools that need to be adapted to each problem to solve.
[Back to top] “It’s The
Chemistry, Stupid !”, or: The Impact of Early
Discovery Patent Applications on the Drug Development Process
Frank Landolt
[Back to top] Recent
Developments in the Synthesis of Nicotinic Acetylcholine Receptor Ligands
Scott R. Breining
The extraordinary pharmacology of nicotine and epibatidine have indicated the potential for nicotinic acetylcholine receptor (nAChR) ligands to serve as a new therapeutic class for a host of CNS disorders. Many such ligands are natural products, or analogs thereof, which represent a significant challenge to the synthetic chemist. Synthesis of such molecules often serves as a showcase to demonstrate the potential of newly developed methodology. This synthetic challenge coupled with the promise of pharmacological activity in compounds possessing the nicotinic pharmacophore has stimulated a great deal of synthetic activity over the last five years. The present report provides an overview of novel synthetic methodology occurring during this period directed toward the synthesis of compounds with presumed affinity for the neuronal nAChR. Syntheses chosen for review here represent the major efforts toward molecules such as epibatidine analogs, anatoxin-a, nicotine and related alkaloids, conformationally constrained nicotine derivatives, cytisine and methyllycaconitine (MLA).
[Back to top] Musings on a4b2
Nicotinic Acetylcholine (nACh) Receptor Pharmacophore Models
Richard A. Glennon, Malgorzata Dukat, Liang Liao
Several pharmacophore models were previously formulated to account for the actions of nicotinic acetylcholinergic (nACh) agents. Most of these models were developed without express consideration of specific radioligand binding data because such data were not available at the time the models were described. In this review, the ability of these models to account for the binding of nicotinic agents at a4b2 nACh receptors (or rat brain receptors for which a4b2 receptors are the major component) is assessed. It seems that none of the early models can adequately explain the binding of these agents as a group. Furthermore, different series of nicotinic agents behave differently depending upon the nature of terminal amine substituents and the spacer that separates the amine from the pyridine ring. A region of bulk tolerance has been identified that accommodates substituents on some nicotinic ligands, but not the same substituents at seemingly corresponding locations of others. The concept of multiple modes of binding has been previously raised and, clearly, cannot yet be discarded. Nevertheless, new vector models seemingly provide a better picture of nACh receptor binding and account for many of the shortcomings associated with the earlier models.
[Back to top] Rational
Understanding of Nicotinic Receptors Drug Binding
Thomas Grutter, Nicolas Le Novere and Jean-Pierre Changeux
The atomic determination of the acetylcholine binding protein (AChBP), a molluscan cholinergic protein, homologous to the amino-terminal extracellular domain of nicotinic receptors (nAChRs), offers opportunities for the modeling of the acetylcholine binding site and its ligands. Recently, we constructed three-dimensional models of the N-terminal part of nAChR and docked in the putative ligand-binding pocket, different agonists (acetylcholine, nicotine and epibatidine) and antagonist (snake -bungarotoxin). These hypothetical docking models offer a structural basis for rational design of drugs differentially binding to resting and active (or desensitized) conformations of the receptor site. These models thus pave the way to investigate, at the molecular level, the exciting challenge of the fast ion channel gating mechanisms by nicotinic agonists.