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The introduction of new pharmaceutical drugs has slowed while money and effort expended by the industry has dramatically increased. We suggest that some of that effort may be inadvertently wasted in drug screening and quantitative structure-activity relationship studies where results can be strongly skewed by the method of liquid handling and the protocol used.
Recent work has demonstrated that dispensing processes have a profound influence on estimates of IC50. What appear to be minor modifications in the design of concentration gradients coupled with long-standing liquid handling procedures have generated a 1.5 to 1,000-fold difference in IC50 showing no correlation or ranking between competing processes. Importantly when such data are used for computational modeling, the computed pharmacophores for each dataset are different and lead to the development of compounds with significantly different structures and chemico-physical properties. Dispensing processes are therefore an important source of error that impacts computational and statistical results. At the same time, commonly-used protocols can generate data can introduce errors independent of the dispensing technology. This paper is an overview of some of the experiences of the authors based on using online chemical compound databases, and publically available data.