Lead new compounds

The enantiophore query used in the search is derived from the CSP and directly built from a 3D structure model of the target CSP molecule, as it can be used today for the determination of new lead compounds [20, 21]. This procedure does not need an important modeling expertise. One can easily recognize the different center types in the receptor in question. These can be hydrogen-bond donors and acceptors, charged... 

After validating the database they used the connectivity map to obtain new information they queried the database with expression signatures from patients and animal models to find small molecules that were already in the database that may mimic or suppress particular diseases. In subsequent studies, they identified geduin, an HSP90 inhibitor, as a new lead compound for the treatment of prostate cancer (59) and ra-pamycin as a potential useful drug for treatment of acute lymphocytic leukemia resistant to dexamethasone (60). 

Schlosser, J., Rarey, M. (2009) Beyond the virtual screening paradigm structure-based searching for new lead compounds. J Chem Inf Model 49, 800-809. 

Wermuth, C.G., Search for new lead compounds the example of the chemical and pharmacological dissection of ami-nopyridazines. J. Heterocycl. Chem., 1998, 35, 1091-1100. 

Methods and approaches that can simultaneously determine mixtures of drug candidates provide a powerful way to select an optimal drug candidate within a specific therapeutic area or a targeted class of compounds. Using relatively simple isolation and chromatography conditions, LC/MS/MS approaches are an effective way to evaluate new lead compounds for subsequent development. Consequently,... 

In addition, the ability of a transcriptional or proteomic profile to provide a biological fingerprint of the function of a compound has been shown recently [94-97], Such studies should prove useful for identifying structure-activity relationships, identifying pharmacophores, and for toxicological assessments of new lead compounds. 

The work of the medicinal chemist is centred around the discovery of new lead compounds with specific medical properties. It includes the development of more effective and safer analogues from both these new and existing lead compounds. This usually involves synthesizing and testing many hundreds of compounds before a suitable compound is produced. It is currently estimated that for every 10000 compounds synthesized one is suitable for medical use. 

Computer modelling has reduced the need to synthesize every analogue of a lead compound. It is also often used retrospectively to confirm the information derived from other sources. Combinatorial chemistry, which originated in the field of peptide chemistry, has now been expanded to cover other areas. The term covers a group of related techniques for the simultaneous production of large numbers of compounds for biological testing. Consequently, it is used for structure action studies and to discover new lead compounds. The procedures may be automated. 

The nature of the action of antimetabolites means that a rational starting point for the design of new drugs is the structure of the normal metabolites used by the cell (Table 7.5). Consequently, SAR studies based on the endogenous metabolite supported by combinatorial synthesis and molecular modelling offer logical routes to new lead compounds and ultimately new drugs. 

A recent review covers the nonclassical polycyclic /3-lactams synthesized with the aim of discovering new lead compounds in the field of antibacterial agents <2000T5743>. Selected compounds 122-127 related to penam or penem structures are shown in Figure 12. 

A9.6.3.1 Choosing an appropriate QSAR implies that the model will yield a reliable prediction for the toxicity or biological activity of an untested chemical. Generally speaking, reliability decreases with increasing complexity of chemical structure, unless a QSAR has been derived for a narrowly defined set of chemicals similar in structure to the candidate substance. QSAR models derived from narrowly defined classes of chemicals are commonly employed in the development of pharmaceuticals once a new lead compound is identified and there is a need to make minor structural modifications to optimize activity (and decrease toxicity). Overall, the objective is make estimates by interpolation rather than extrapolation. 

---