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Advances in Computational Polypharmacology.

ABSTRACT: In drug discovery, polypharmacology encompasses the use of small molecules with defined multi-target activity and in vivo effects resulting from multi-target engagement. Multi-target compounds are often efficacious in the treatment of complex diseases involving target and pathway networks, but might also elicit unwanted side effects. Computational approaches such as target prediction or multi-target ligand design have been used to support polypharmacological drug discovery. In addition to efforts directed at the identification or design of new multi-target compounds, other computational investigations have aimed to differentiate such compounds from potential false-positives or explore the molecular basis of multi-target activities. Herein, a concise overview of the field is provided and recent advances in computational polypharmacology through machine learning are discussed.

SUBMITTER: Feldmann C

PROVIDER: S-EPMC10078381 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Advances in Computational Polypharmacology.

Feldmann Christian C Bajorath Jürgen J

Molecular informatics 20220906 12

In drug discovery, polypharmacology encompasses the use of small molecules with defined multi-target activity and in vivo effects resulting from multi-target engagement. Multi-target compounds are often efficacious in the treatment of complex diseases involving target and pathway networks, but might also elicit unwanted side effects. Computational approaches such as target prediction or multi-target ligand design have been used to support polypharmacological drug discovery. In addition to effort ...[more]

PMID: 36002382

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Project description:The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with protein inhibition. Recent advancements in the biotech and pharmaceutical sectors have led to the development of compounds that are currently in human trials, with some showing promising clinical results. However, the use of computational tools in TPD is still limited, as it has distinct characteristics compared with traditional computational drug design methods. TPD involves creating a ternary structure (protein-degrader-ligase) responsible for the biological function, such as ubiquitination and subsequent proteasomal degradation, which depends on the spatial orientation of the protein of interest (POI) relative to E2-loaded ubiquitin. Modeling this structure necessitates a unique blend of tools initially developed for small molecules (e.g., docking) and biologics (e.g., protein-protein interaction modeling). Additionally, degrader molecules, particularly heterobifunctional degraders, are generally larger than conventional small molecule drugs, leading to challenges in determining drug-like properties like solubility and permeability. Furthermore, the catalytic nature of TPD makes occupancy-based modeling insufficient. TPD consists of multiple interconnected yet distinct steps, such as POI binding, E3 ligase binding, ternary structure interactions, ubiquitination, and degradation, along with traditional small molecule properties. A comprehensive set of tools is needed to address the dynamic nature of the induced proximity ternary complex and its implications for ubiquitination. In this Perspective, we discuss the current state of computational tools for TPD. We start by describing the series of steps involved in the degradation process and the experimental methods used to characterize them. Then, we delve into a detailed analysis of the computational tools employed in TPD. We also present an integrative approach that has proven successful for degrader design and its impact on project decisions. Finally, we examine the future prospects of computational methods in TPD and the areas with the greatest potential for impact.

Dataset Information

Advances in Computational Polypharmacology.

Publications

Advances in Computational Polypharmacology.

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