An omics perspective to the molecular mechanisms of anticancer metallo-drugs in the computational microscope era

ABSTRACT

Introduction: Metallo-drugs have attracted enormous interest for cancer treatment. The achievements of this drug-type are summarized by the success story of cisplatin. That being said, there have been many drawbacks with its clinical use, which prompted decades worth of research efforts to move towards safer and more effective agents, either containing platinum or different metals.

Areas covered: In this review, the authors provide an atomistic picture of the molecular mechanisms involving selected metallo-drugs from structural and molecular simulation studies. They also provide an omics perspective, pointing out many unsettled aspects of the most relevant families of metallo-drugs at an epigenetic level.

Expert opinion: Molecular simulations are able to provide detailed information at atomistic and temporal (ps) resolutions that are rarely accessible to experiments. The increasing accuracy of computational methods and the growing performance of computational platforms, allow us to mirror wet lab experiments in silico. Consequently, the molecular mechanisms of drugs action/failure can be directly viewed on a computer screen, like a ‘computational microscope’, allowing us to harness this knowledge for the design of the next-generation of metallo-drugs.

KEYWORDS:

• Cisplatin
• copper
• ruthenium
• metallo-drug
• DNA
• drug discovery
• free energy calculations
• G-quadruplex
• metadynamics
• molecular dynamics
• NAMI-A
• nucleosome
• platinum
• QM/MM

Article highlights

• Molecular simulations provide an atomic-level understanding of the molecular mechanisms of metallo-drugs, and can be further employed for their rational design.

• Conventionally, metallo-drugs are believed to target mostly canonical B-DNA; as such, most of the literature studies focus on their binding to short DNA oligonucleotides (naked DNA).

• Experimental and computational studies have demonstrated that metallo-drug binding at a nucleosome level is remarkably different with respect to naked DNA, and can help to rationalize the mechanism of action of selected drugs.

• Recent studies are starting to address the binding of metallo-drugs to rare DNA motifs that are involved in aging and cancer, such as DNA G-quadruplexes.

• The interactions between metallo-drugs and proteins have been largely overlooked. There are only few examples of experimental and computational studies discussing the transport and the resistance mechanisms of metallo-drugs.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors thank the Associazione Italiana per la Ricerca sul Cancro (AIRC) for financial support (My first AIRC grant no: 17134).