Changing Trends in Computational Drug Repositioning

Abstract

Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated—“The most fruitful basis for the discovery of a new drug is to start with an old drug”. However, rational design of drug mixtures poses formidable challenges because of the lack of or limited information about in vivo cell regulation, mechanisms of genetic pathway activation, and in vivo pathway interactions. Hence, most of the successfully repositioned drugs are the result of “serendipity”, discovered during late phase clinical studies of unexpected but beneficial findings. The connections between drug candidates and their potential adverse drug reactions or new applications are often difficult to foresee because the underlying mechanism associating them is largely unknown, complex, or dispersed and buried in silos of information. Discovery of such multi-domain pharmacomodules—pharmacologically relevant sub-networks of biomolecules and/or pathways—from collection of databases by independent/simultaneous mining of multiple datasets is an active area of research. Here, while presenting some of the promising bioinformatics approaches and pipelines, we summarize and discuss the current and evolving landscape of computational drug repositioning.

Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation

“…Most of the compounds used on these studies were specifically chosen for their ability to target key players of the ERQC and ERAD pathways, the mechanisms involved in the active degradation of mutant proteins, or to rescue other misfolded proteins such as in the case of CFTR correctors 16 . Even though specific mechanisms can be involved in the recognition of the misfolding structure of each disease-causing protein, the above mentioned studies demonstrates that some common features make possible to repurpose drugs from one to the other disease 23 . Here, we performed a drug screening on the most frequent LGMD2D causing mutation (p.R77C) as a platform to identify drugs that would also benefit other misfolding diseases.…”

Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration

“…Nevertheless, based on a more straightforward synthesis route, scalable manufacturing, and other practical considerations, an inhalable formulation of CFZ-HCl microcrystals could offer a more viable approach for pharmaceutical product development. As a wise man once said: “the most fruitful basis for the discovery of a new drug is to start with an old drug [29,30,31]”.…”

(Q)SAR Models of HIV-1 Protein Inhibition by Drug-Like Compounds

“…Discovery of novel pharmaceutical agents is always based on existing knowledge about the mechanisms of the disease-molecular targets that should be affected to normalize the pathological process and ligands that may interact with the targets of interest [1]. Currently, no investigational drug is studied without some contribution of in silico methods [2].…”