Current Topics in Medicinal Chemistry - Volume 4, Issue 6, 2004

HIT-TO-LEAD: DRIVING FORCES FOR THE MEDICINAL CHEMIST Drug discovery is a succession of design, synthesis and selection steps. The understanding at a molecular level of the biological processes underlying many diseases has lead to a miniaturization of the bioassays and a dramatic increase in throughput, at the initial step of selection. During the shift from animal testing to target-based assays much releva Read More

Nicotinic Acetylcholine Receptors: Ligand Design Issues Nearly 100 years have passed since Langley suggested the existence of nicotinic acetylcholine receptors (nAChRs) [1]. Only in the past decade has enough evidence accumulated to demonstrate, beyond the anecdotal, the potential of nAChR-based therapeutics to address significant unmet medical need. Areas of intense academic and pharmaceutical indust Read More

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 Read More

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 ar Read More

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 molecul Read More

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 n Read More

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 α4β2 nACh receptors ( Read More

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 Nterminal part of nAChR and docked in the putative ligand-binding pocket, different ag Read More