Binding site comparisons for target-centered drug discovery

ABSTRACT

Introduction: The success of binding site comparisons in drug discovery is based on the recognized fact that many different proteins have similar binding sites. Indeed, binding site comparisons have found many uses in drug development and have the potential to dramatically cut the cost and shorten the time necessary for the development of new drugs.

Areas covered: The authors review recent methods for comparing protein binding sites and their use in drug repurposing and polypharmacology. They examine emerging fields including the use of binding site comparisons in precision medicine, the prediction of structured water molecules, the search for targets of natural compounds, and their application in the development of protein-based drugs by loop modeling and for comparison of RNA binding sites.

Expert opinion: Binding site comparisons have produced many interesting results in drug development, but relatively little work has been done on protein–protein interaction sites, which are particularly relevant in view of the success of biological drugs. Growth of protein loop modeling for modulating biological drugs is anticipated. The fusion of currently distinct methods for the comparison of RNA and protein binding sites into a single comprehensive approach could allow the search for new selective ribosomal antibiotics and initiate pharmaceutical research into other nucleoproteins.

KEYWORDS:

• Binding site comparison
• drug repurposing
• polypharmacology
• precision medicine
• conserved water
• natural products
• biological drugs
• RNA motifs

Article highlights

• Binding site comparison allows drug repurposing, an approach that is increasingly gaining use in the treatment of rare and neglected diseases, as it allows significantly faster development than conventional drug development.

• Binding site comparison allows the design of polypharmacological drugs that could improve the treatment of cancer and neurodegenerative diseases.

• Binding site comparison enables the proteome-wide prediction of binding sites and ligands of proteins and allows the determination of the effects of sequence variants on the binding of drugs and development of diseases.

• Binding site comparison permits the identification of targets for natural products.

• Binding site comparison facilitates the prediction of new conserved structured water molecules that are important for the activity of kinases.

• Binding site comparison enables protein loop modeling in the development of biological drugs and allows prediction of RNA functions and the development of selective ribosome-targeting antibiotics.

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Declaration of interest

J Konc has 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

J Konc is supported by the Slovenian Research Agency under project number L7-8269 and research core funding number P1-0002.