Molecular hybridization: a powerful tool for multitarget drug discovery

ABSTRACT

Introduction

The current drug discovery paradigm of ‘one drug, multiple targets’ has gained attention from both the academic medicinal chemistry community and the pharmaceutical industry. This is in response to the urgent need for effective agents to treat multifactorial chronic diseases. The molecular hybridization strategy is a useful tool that has been widely explored, particularly in the last two decades, for the design of multi-target drugs.

Areas covered

This review examines the current state of molecular hybridization in guiding the discovery of multitarget small molecules. The article discusses the design strategies and target selection for a multitarget polypharmacology approach to treat various diseases, including cancer, Alzheimer’s disease, cardiac arrhythmia, endometriosis, and inflammatory diseases.

Expert opinion

Although the examples discussed highlight the importance of molecular hybridization for the discovery of multitarget bioactive compounds, it is notorious that the literature has focused on specific classes of targets. This may be due to a deep understanding of the pharmacophore features required for target binding, making targets such as histone deacetylases and cholinesterases frequent starting points. However, it is important to encourage the scientific community to explore diverse combinations of targets using the molecular hybridization strategy.

KEYWORDS:

• Molecular design
• molecular hybridization
• drug discovery
• hybrids
• dual inhibitors
• multitarget drugs

Article highlights

• Molecular hybridization is a powerful tool for the rational design of multitarget ligands by combining pharmacophore features of different templates.

• A proper structure-activity relationship must be carried out to identify multitarget compounds with balanced pharmacological activities.

• Most studies on multitarget hybrids have focused on cancer and neurodegeneration, particularly for the treatment Alzheimer’s disease.

• Kinases, histone deacetylases and cholinesterases are important platforms for multitarget hybrid compound design, which is related to the understanding of the structural factors that lead to the effective inhibition of these targets.

• The correct choice of targets should be based on network pharmacology studies to identify targets that can generate synergism when simultaneously modulated. This approach enables the discovery of hybrids that can represent significant therapeutic innovations.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer disclosures

One referee is an employee of Charles River Laboratories. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (award no. 304.811/2022-0), the Departamento de Ciência e Tecnologia (DECIT) of the Ministry of Health, Brazil, Ministry of Health, Brazil, the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (award no. E-26/010.001273/2016 and SEI-260003/003613/2022) and the Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (award no. 465.249/2014-0).