Drug discovery research studies

Completed drug discovery research studies indicate that a compound, or class of compounds, mediates a disease process and has potential as human therapeutic agent. Is this lead compound now ready to be transferred from the discovery area to a preclinical development group Should additional, nondefinitive experiments be conducted to characterize more fully the properties of the lead candidate If more studies are considered necessary, what experiments should be done ... 

The isolation of the benzolactone enamide salicylihalamide A 17101 (Scheme 6.1 Part 2) was guided by the NCI s Drug Discovery Research and Development, Developmental Therapeutics Program screen for differential cytotoxicity, which showed that the Australian sample of Haliclona possessed a unique 60 cell line profile. Nanomolar potency was evident in the melanoma cell lines (GI50 = 7 nM) and a COMPARE analysis of the 60 cell line data indicated vascular ATPase (V-ATPase) activity potential. Further study of this structure class determined that salicylihalamide A is equipotent to the V-ATPase standards bafilomycin A and concanamycin A,273 but unlike these standards, selectively inhibits mammalian V-ATPases. 

In this chapter, different VS studies and their results are discussed and it is attempted to critically evaluate the opportunities and limitations of VS, with a particular focus on its practical relevance and value. A general perspective upfront As proponents and developers of computational methods and also as VS practitioners, our view of the VS field should not come across as intentionally negative. Rather, we understand the critique as a plea for this field. However, we are convinced that it will be essential to raise the scientific standards of VS and the awareness of its limitations in order to provide a foundation for further growth of the field and for higher impact on drug discovery research. 

Pharmacokinetic studies in drug discovery research deal with the measurement of the drug eoneentration in plasma with respeet to time and the key parameters involved are volume of distribution (Fd), bioavailability (F), exposure (measured as the area under the curve or AUC), maximum plasma concentration attained (Cmax), time of maximum drug concentration (T ax). clearance (Cl) and half-life ( 1/2). These parameters and their role in drug discovery have been diseussed in detail in most text books related to drug metabolism and pharmaeokineties (DMPK), and have been discussed only briefly here. Eaeh of the above are defined as follows ... 

Recent studies indicated that in addition to the regnlation of postprandial gly-cemia, DPP-IV may have pleiotropic effects (e.g., obesity, tumor growth, and HIV infection), which makes it an attractive target for drug discovery research [27-32]. DPP-IV inhibitors block the degradation of GLP-1 and inhibit the inactivation of several other peptides that may have vasoactive and cardioprotective effects... 

---