High-resolution view of compound promiscuity

Compound promiscuity is described as the ability of a Staurosporine tiny molecule to specifically interact with several organic targets. So-outlined promiscuity is pertinent Staurosporine for drug discovery simply because it gives the molecular foundation of polypharmacology, which is increasingly implicated in the therapeutic efficacy of medications. Recent studies have analyzed different elements of compound promiscuity on the foundation of at present available activity data. In this commentary, we existing consider-property messages from these studies augmented with new benefits to make a comprehensive image of compound promiscuity that may provide as a reference for even more conversations and investigation pursuits.

Polypharmacology is an rising concept in drug discovery1,two. It is generally approved that medication usually elicit their therapeutic consequences by way of interactions with distinct targets and the ensuing modulation of multiple signaling pathways. In some therapeutic places this kind of as oncology, polypharmacology is intensely exploited, for case in point, by means of the use of promiscuous ATP site-directed protein kinase inhibitors3. In other regions, this sort of as the treatment method of infectious or chronic inflammatory conditions, obtaining a large degree of concentrate on selectivity of drug candidates plays a main position.

Key final results of compound promiscuity examination

General public info sources for compound promiscuity evaluation mentioned herein have been ChEMBL10, the significant repository of compound action knowledge from medicinal chemistry (currently in May 2013 made up of 1,295,510 compounds with a total of 11,420,351 action annotations), the PubChem BioAssay database11, the significant repository of screening information (with far more than 3300 confirmatory assays), and DrugBank12, which currently is made up of 1518 accepted and 5080 experimental medication.

It is essential to notice that gathering all action annotations for a compound documented in the literature which includes, for example, reporter gene or other cell-dependent assays is at ideal supplying a evaluate of assay promiscuity, but not of distinct interactions with various targets9. For that reason, it is usually essential to apply info confidence requirements this kind of as the existence of nicely-described action measurements or proof for immediate ligand-focus on interactions9 (as presented in ChEMBL as activity info filters).
Exercise measurement dependence

When checking the expansion of compound action information in ChEMBL in excess of a interval of a lot more than two a long time from its first release (January 2010) to launch thirteen (Might 2012), a substantial improve in the amount of promiscuous compounds was detected13. Nevertheless, by quantifying compound-primarily based focus on interactions, it was established that the improve in compounds with action towards targets from distinct households was mainly because of to (assay-dependent) IC50 measurements, relatively than (assay-unbiased) equilibrium constants (Ki values)thirteen. IC50 values are simpler to establish than Ki values and supply the readout of most main biochemical assays (other than one-level screening assays), which may well at least in component rationalize increased concentrate on coverage and the IC50-dependent enhance in compound promiscuity across distinct families. Nonetheless, it can also not be excluded that clear promiscuity in distinct assays is larger on the basis of IC50 measurements, provided their assay dependence (and usually limited precision). Regardless, the type of activity measurements that are taken into account influences the end result of promiscuity examination.