Trends in Chemistry
Volume 1, Issue 7, October 2019, Pages 644-655
Journal home page for Trends in Chemistry

Review
Extrapolating the Fragment-Based Approach to Inorganic Drug Discovery

https://doi.org/10.1016/j.trechm.2019.05.001Get rights and content

Highlights

  • The fragment-based approach has delivered new targeted drugs in medicinal organic chemistry but has not yet been systematically applied to metal-based drugs.

  • Bimetallic compounds with the ability to form strong covalent interactions with biomolecules have been shown to possess unique biological profiles.

  • Heterobimetallic compounds that are able to bridge different classes of biomolecules (e.g., DNA to proteins) have recently been designed.

  • Crosslinking diverse biomolecules (i.e., DNA, proteins, and enzymes) presents a greater challenge to cellular repair mechanisms and may lead to new drugs that are able to overcome chemoresistance.

The fragment-based approach is a well-established strategy for organic drug discovery. Recent studies have shown that this approach also has considerable potential in medicinal inorganic chemistry, and yet the approach has not been formally described. Here, we describe selected compounds that form (or have potential to form) intra- or inter-DNA–DNA, DNA–protein, and protein–protein crosslinks. Such dual interactions provide a powerful way to generate metal-based drugs with superior efficacies to those currently used. We demonstrate that the fragment-based approach represents an ideal way to design these bioactive compounds. In this review, we point out the limitations of current examples and delineate key components that might lead to more effective compounds (i.e., compounds that are more selective and have stronger binding affinities for specific biomolecular targets).

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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