Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs

Abstract

The search for Golgi α-mannosidase II (GMII) potent and specific inhibitors has been a focus of many studies for the past three decades since this enzyme is a key target for cancer treatment. α-Mannosidases, such as those from Drosophila melanogaster or Jack bean, have been used as functional models of the human Golgi α-mannosidase II (hGMII) because mammalian mannosidases are difficult to purify and characterize experimentally. Meanwhile, computational studies have been seen as privileged tools able to explore assertive solutions to specific enzymes, providing molecular details of these macromolecules, their protonation states and their interactions. Thus, modelling techniques can successfully predict hGMII 3D structure with high confidence, speeding up the development of new hits. In this study, Drosophila melanogaster Golgi mannosidase II (dGMII) and a novel human model, developed in silico and equilibrated via molecular dynamics simulations, were both opposed for docking. Our findings highlight that the design of novel inhibitors should be carried out considering the human model’s characteristics and the enzyme operating pH. A reliable model is evidenced, showing a good correlation between K_i/IC₅₀ experimental data and theoretical ΔG_binding estimations in GMII, opening the possibility of optimizing the rational drug design of new derivatives.

Communicated by Ramaswamy H. Sarma

Keywords:

• Golgi α-mannosidase II
• iminosugars
• molecular dynamics simulations
  
• molecular docking
• pH
• structural assessment
• inhibitors

Authors’ contribution

The manuscript was written through the contributions of all authors. All authors have given approval for the final version of the manuscript. Drogalin conducted the simulations, docking and analysis. Monteiro, Alves, and Castro contributed to the overall design and conceptualization of the project; Castro also acts as supervisor of modelling work.

Disclosure statement

The authors confirm that this article’s content has no conflict of interest.

Data availability statement

Parts of the Graphical Abstract were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). Other parts were taken from https://www.pngegg.com/ and https://imgbin.com/png/T1vh1JNL/fly-mosquito-insect-sensillum-png free image data banks.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study was supported by the Portuguese Foundation for Science and Technology (FCT) for funding the PhD fellowship SFRH/BD/150695/2020 assigned to Artem Drogalin by the SPQ within the international year of the periodic table. Thanks are due to FCT and FEDER (European Fund for Regional Development)-COMPETE-QRENEU for financial support through the Chemistry Research Centre of the University of Minho (Ref. CQ/UM (UID/QUI/00686/2020)). Castro thanks FCT under the scope of the strategic funding of UIDB/04469/2020 unit, and by LABBELS – Associate Laboratory in Biotechnology, Bioengineering and Microelectromechanical Systems, LA/P/0029/2020. This research was developed with the support of computing facilities provided by the Project Search-ON2 must include in their publications (papers and thesis) the following reference: “Search-ON2: Revitalization of HPC infrastructure of UMinho” (NORTE-07-0162-FEDER-000086), co-funded by the North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF).