In silico study of subtilisin-like protease 1 (SUB1) from different Plasmodium species in complex with peptidyl-difluorostatones and characterization of potent pan-SUB1 inhibitors

Journal of Molecular Graphics & Modelling
Simone BrogiStefania Butini

Abstract

Plasmodium falciparum subtilisin-like protease 1 (SUB1) is a novel target for the development of innovative antimalarials. We recently described the first potent difluorostatone-based inhibitors of the enzyme ((4S)-(N-((N-acetyl-l-lysyl)-l-isoleucyl-l-threonyl-l-alanyl)-2,2-difluoro-3-oxo-4-aminopentanoyl)glycine (1) and (4S)-(N-((N-acetyl-l-isoleucyl)-l-threonyl-l-alanylamino)-2,2-difluoro-3-oxo-4-aminopentanoyl)glycine (2)). As a continuation of our efforts towards the definition of the molecular determinants of enzyme-inhibitor interaction, we herein propose the first comprehensive computational investigation of the SUB1 catalytic core from six different Plasmodium species, using homology modeling and molecular docking approaches. Investigation of the differences in the binding sites as well as the interactions of our inhibitors 1,2 with all SUB1 orthologues, allowed us to highlight the structurally relevant regions of the enzyme that could be targeted for developing pan-SUB1 inhibitors. According to our in silico predictions, compounds 1,2 have been demonstrated to be potent inhibitors of SUB1 from all three major clinically relevant Plasmodium species (P. falciparum, P. vivax, and P. knowlesi). We next derived multiple str...Continue Reading

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Citations

Aug 25, 2016·Future Medicinal Chemistry·Margherita BrindisiSandra Gemma
Aug 25, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Simone Brogi
Apr 8, 2020·Parasites & Vectors·Nobuko ArisueToshihiro Horii
Mar 21, 2019·Frontiers in Microbiology·Manasi MishraShailja Singh
May 16, 2017·Frontiers in Chemistry·Giulia ChemiMargherita Brindisi
Nov 18, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Edson Roberto da SilvaClaudia do Carmo Maquiaveli
Dec 29, 2020·Expert Opinion on Drug Discovery·Probir Kumar OjhaKunal Roy

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Methods Mentioned

BETA
X-ray

Software Mentioned

ConfGen
Schrödinger Maestro
MacroModel ( MacroModel
MacroModel
Glide
- E )
LigPrep
Glide XP
GOLD
ConGen

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