Empirical Drug Discovery

Empirical drug discovery, despite its successes, is not without intrinsic problems the identification of a lead compound is divorced from an understanding of its mechanism of action, making lead optimization difficult since there is no easily quantifiable way to ascertain whether an analog will have greater effect. Additionally, the value of an empirical screen depends on its predictive ability. In some cases, such as acid hyposecretion or H2-receptor binding assays. 

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Singh SB, Barrett JF. (2006) Empirical antibacterial drug discovery — foundation in natural products. Biochem Pharmacol 71 1006-1015. 

Effective structure-activity relationship (SAR) generation is at the centre of any medicinal chemistry campaign. Much work has been done to devise effective methods to explain and explore SAR data for medicinal chemistry teams to drive the design cycles within drug discovery projects (1). Recent work on SAR generation highlights the commonly observed discontinuity of SAR and bioactivity data, the so-called activity cliffs (2). This also emphasises the need to empirically determine SAR for each lead... 

To achieve the greatest improvements in drug discovery efficiency, empirical data of various kinds must be collected throughout the iterative refinement process. It is desirable to obtain more accurate dissociation constants rather than IC50 or single-point percent-inhibition values. In addition, the 3-dimensional structures of interesting target—inhibitor complexes are determined... 

We shall assume, rather arbitrarily for the purpose of this discussion, that the starting point of pharmaceutical innovation is the development of a new biologic concept (or a new approach to an existing concept) that is potentially therapeutically exploitable. Moving from the earliest and most a priori to the later and more empirical methods of drug discovery, the following types of innovation can be distinguished. 

Miller JM, Blackburn AC, Shi Y et al. (2002) Semi-empirical relationships between effective mobility, charge, and molecular weight of pharmaceuticals by pressure-assisted capillary electrophoresis Applications in drug discovery. Electrophoresis 23 2833-2841... 

Table 1 Empirical rules-of-thumb to estimate the suitability of compounds at different stages of drug discovery based on structural properties...

Once a medical need and market niche are identified, and a particular therapeutic area chosen, the biological research begins. It is during this first stage of drug discovery that anecdotal clinical observations, empirical outcomes and data from folk medicine are often employed, if only as direction-finding tools. 

Since the evolution of traditional pharmacopeias has been predicated upon time-honored empirical testing, customary herbal remedies continue to be used by a vast majority of the world s population who depend on traditional medicine for their primary needs. Worldwide, the practice of herbalism continues to expand, and it has been estimated that the industry estimated at 60 billion today will significantly expand during this century (World Health Organization [WHO], 2004). To prove parameters of efficacy, more and more are being clinically evaluated in the context of use. Many have also been found to possess specific bioreactive compounds linked to their medical value, which in turn not only has verified their therapeutic worth, but also has led to new and significant drug discoveries (Lewis and... 

Because of this limited number of interactions, kinesins have a moderate affinity for ATP Eg5 has a ICm of approximately 21 pM for ATP (132). While the ATP-binding pocket has a reasonable volume of approximately 1,980 A3 and significant chemical and structural features to define it as a druggable binding site, empirical evidence suggests that it is not the most amenable site on the macromolecule for drug discovery. 

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