Medicinal chemistry is a complex science that lies at the interface of many fields of research and at the very heart of drug discovery, with property
relationships based on chemical structure at its core. It is clear that the effective capture and dissemination of
medicinal chemistry knowledge and experience will be a key differentiator among pharmaceutical organizations and crucial for the future success in delivering effective and safe drug candidates. Therefore, in 2005 we developed ROCK (Roche
medicinal chemistry knowledge), an internal user-friendly and peer-reviewed Wiki-like application to capture, browse and search tacit knowledge, key discoveries and property effects related to chemical structure, which is used as a primary source for addressing challenges faced in drug design. Drug-induced liver injury (DILI) is a leading cause of
drugs failing during
clinical trials and being withdrawn from the market. Comparative analysis of
drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287
drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed
drugs for supporting
drug discovery and
biomarker development. All
cells necessarily contain tens, if not hundreds, of carriers for nutrients and intermediary metabolites, and the human
genome codes for more than 1000 carriers of various kinds. Here, we illustrate using a typical literature example the widespread but erroneous nature of the assumption that the ‘background’ or ‘passive’ permeability to
drugs occurs in the absence of carriers. Comparison of the rate of drug transport in natural versus artificial membranes shows discrepancies in absolute magnitudes of 100-fold or more, with the carrier-containing
cells showing the greater permeability. Expression profiling data show exactly which carriers are expressed in which tissues. The recognition that
drugs necessarily require carriers for uptake into
cells provides many opportunities for improving the effectiveness of the
drug discovery process.
Relevant Topics in Neuroscience & Psychology