What are the challenges with multi-targeted drug design for complex diseases?

ABSTRACT

Introduction

Current findings on multifactorial diseases with a complex pathomechanism confirm that multi-target drugs are more efficient ways in treating them as opposed to single-target drugs. However, to design multi-target ligands, a number of factors and challenges must be taken into account.

Areas covered

In this perspective, we summarize the concept of application of multi-target drugs for the treatment of complex diseases such as neurodegenerative diseases, schizophrenia, diabetes, and cancer. We discuss the aspects of target selection for multifunctional ligands and the application of in silico methods in their design and optimization. Furthermore, we highlight other challenges such as balancing affinities to different targets and drug-likeness of obtained compounds. Finally, we present success stories in the design of multi-target ligands for the treatment of common complex diseases.

Expert opinion

Despite numerous challenges resulting from the design of multi-target ligands, these efforts are worth making. Appropriate target selection, activity balancing, and ligand drug-likeness belong to key aspects in the design of ligands acting on multiple targets. It should be emphasized that in silico methods, in particular inverse docking, pharmacophore modeling, machine learning methods and approaches derived from network pharmacology are valuable tools for the design of multi-target drugs.

KEYWORDS:

• Drug design
• multifactorial diseases
• multi-target drugs
• polypharmacology

Article highlights

• Treatment of complex diseases requires multi-target drugs to reflect the complex pathomechanism of these disorders.

• Appropriate target selection is a key for a successful design of an efficient multi-target drug.

• Other important challenges include activity balancing and designing a drug-like compound with a desired physicochemical profile.

• In silico approaches constitute a valuable support in the design of multifunctional ligands.

• Current efforts on multi-target drug design involve i.a. compounds for potential treatment of Alzheimer’s disease, Parkinson’s disease, schizophrenia, diabetes, depression and cancer.

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 reviewer declares that they have employment with Servier while another is employed by Evotec. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are supported by an OPUS grant from the National Science Center (NCN, Poland), [grant number 2017/27/B/NZ7/01767 (to AA Kaczor)].