In Silico Elucidation of the Molecular Mechanism Defining the Adverse Effect of Selective Estrogen Receptor Modulators

Early identification of adverse effect of preclinical and commercial drugs is crucial in developing highly efficient therapeutics, since unexpected adverse drug effects account for one-third of all drug failures in drug development. To correlate protein–drug interactions at the molecule level with their clinical outcomes at the organism level, we have developed an integrated approach to studying protein–ligand interactions on a structural proteome-wide scale by combining protein functional site similarity search, small molecule screening, and protein–ligand binding affinity profile analysis. By applying this methodology, we have elucidated a possible molecular mechanism for the previously observed, but molecularly uncharacterized, side effect of selective estrogen receptor modulators (SERMs). The side effect involves the inhibition of the Sacroplasmic Reticulum Ca2+ ion channel ATPase protein (SERCA) transmembrane domain. The prediction provides molecular insight into reducing the adverse effect of SERMs and is supported by clinical and in vitro observations. The strategy used in this case study is being applied to discover off-targets for other commercially available pharmaceuticals. The process can be included in a drug discovery pipeline in an effort to optimize drug leads and reduce unwanted side effects.: Early identification of the side effects of preclinical and commercial drugs is crucial in developing highly efficient therapeutics, as unexpected side effects account for one-third of all drug failures in drug development and lead to drugs being withdrawn from the market. Compared with the experimental identification of off-target proteins that cause side effects, computational approaches not only save time and costs by providing a candidate list of potential off-targets, but also provide insight into understanding the molecular mechanisms of protein–drug interactions. In this paper we describe an integrated approach to identifying similar drug binding pockets across protein families that have different global shapes. In a case study, we elucidate a possible molecular mechanism for the observed side effects of selective estrogen receptor modulators (SERMs), which are widely used to treat and prevent breast cancer and other diseases. The prediction provides molecular insight into reducing the side effects of SERMs and is supported by clinical and biochemical observations. The strategy used in this case study is being applied to discover off-targets for other commercially available pharmaceuticals and to repurpose existing safe pharmaceuticals to treat different diseases. The process can be included in a drug discovery pipeline in an effort to optimize drug leads, reduce unwanted side effects, and accelerate development of new drugs.