Trends in Chemistry
ReviewExtrapolating the Fragment-Based Approach to Inorganic Drug Discovery
Section snippets
Why Is the Fragment-Based Approach (FBA) a Viable Tool for Drug Discovery?
The fragment-based approach (FBA) is a well-established strategy in drug discovery [1], in which the weak binding of small molecules (typically <300 Da) to specific proteins is enhanced through the introduction of appropriate covalently linked weakly binding complementary fragments [2]. Such an approach has led to the discovery of potent drug candidates, such as Zelboraf®, used to treat late-stage melanoma by inhibiting B-Raf kinase carrying the V600E mutation, and venetoclax, which binds to
Homobimetallic Platinum Compounds
To apply the FBA to inorganic (metal-based) systems, a drug candidate(s) with well-documented binding preferences is required. Cis-diamminedichloroplatinum(II) (i.e., cisplatin, Figure 3) is a bifunctional alkylating agent which is prominent in the treatment of a variety of cancers, including ovarian, testicular, lung, and brain cancers [9]. As a mononuclear complex, cisplatin possesses short-range intra- or interstrand DNA crosslinking capabilities, predominantly 1,2-intrastand crosslinks
FBA Applied to Heterobimetallic Complexes
Connecting two different metal fragments is generally more synthetically challenging than linking the same metal fragments, but heterobimetallic systems potentially provide the greatest benefits and more closely mimic the FBA associated with small organic drugs. Combining medicinally relevant metals, such as platinum(II), ruthenium(III/II), or gold(I), could lead to species with the ability to form more specific protein–protein, DNA–DNA, and DNA–protein crosslinks. Although numerous examples of
Concluding Remarks
Although most of the bimetallic complexes described in this review were not specifically designed with the FBA in mind, they nonetheless may be classified as FBA-inspired compounds. We believe that lessons from the widely applied FBA encountered in medicinal organic chemistry should be increasingly applied to inorganic compounds, and in this respect we have highlighted compounds that illustrate the types of possibilities available. It is apparent, however, that greater specificity of the
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