Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma.

Filipe G A Estrada,Alfonso T García-Sosa,Natália Aniceto,Rita C Guedes,Silvia Miccoli

doi:10.3390/molecules26185574

Filipe G A Estrada, Alfonso T García-Sosa + Show 3 more

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https://doi.org/10.3390/molecules26185574

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Abstract

Multiple myeloma is an incurable plasma cell neoplastic disease representing about 10–15% of all haematological malignancies diagnosed in developed countries. Proteasome is a key player in multiple myeloma and proteasome inhibitors are the current first-line of treatment. However, these are associated with limited clinical efficacy due to acquired resistance. One of the solutions to overcome this problem is a polypharmacology approach, namely combination therapy and multitargeting drugs. Several polypharmacology avenues are currently being explored. The simultaneous inhibition of EZH2 and Proteasome 20S remains to be investigated, despite the encouraging evidence of therapeutic synergy between the two. Therefore, we sought to bridge this gap by proposing a holistic in silico strategy to find new dual-target inhibitors. First, we assessed the characteristics of both pockets and compared the chemical space of EZH2 and Proteasome 20S inhibitors, to establish the feasibility of dual targeting. This was followed by molecular docking calculations performed on EZH2 and Proteasome 20S inhibitors from ChEMBL 25, from which we derived a predictive model to propose new EZH2 inhibitors among Proteasome 20S compounds, and vice versa, which yielded two dual-inhibitor hits. Complementarily, we built a machine learning QSAR model for each target but realised their application to our data is very limited as each dataset occupies a different region of chemical space. We finally proceeded with molecular dynamics simulations of the two docking hits against the two targets. Overall, we concluded that one of the hit compounds is particularly promising as a dual-inhibitor candidate exhibiting extensive hydrogen bonding with both targets. Furthermore, this work serves as a framework for how to rationally approach a dual-targeting drug discovery project, from the selection of the targets to the prediction of new hit compounds.

Highlights

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterised by the clonal proliferation of plasma cells producing a monoclonal immunoglobulin, with devastating complications such as bone diseases, hypercalcemia, renal failure, anemia, and infections
Comparing the physicochemical profile of both sets of inhibitors shows that EZH2 inhibitors tend to have smaller polar surface (TPSA) values as well as fewer rotatable bonds
Upon inspecting the Murcko scaffold content in both datasets, we identified no overlap between Proteasome 20S (P20S) and EZH2 inhibitors (Figure 3B)

Summary

Introduction

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterised by the clonal proliferation of plasma cells producing a monoclonal immunoglobulin, with devastating complications such as bone diseases, hypercalcemia, renal failure, anemia, and infections. It accounts for approximately 1% of neoplastic diseases and represents around 10–15% of all haematological malignancies diagnosed in developed countries [1]. Simultaneous inhibition of multiple targets is an established therapeutic strategy able to improve the efficacy, either additively or synergistically, while being less prone to the emergence of drug resistance mutations, and reducing adverse reactions, resulting in a superior clinical activity profile when compared to single-agent therapies, and may be a novel opportunity in the treatment of MM [7]. The challenge lies in discovering the appropriate targets and compounds with an appropriate multitarget profile, which are two of the main hurdles in the discovery and clinical development of these drugs

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