10779/crick.12607946.v1
Simone Brogi
Simone
Brogi
Simone Giovani
Simone
Giovani
Margherita Brindisi
Margherita
Brindisi
Sandra Gemma
Sandra
Gemma
Ettore Novellino
Ettore
Novellino
Giuseppe Campiani
Giuseppe
Campiani
Michael J Blackman
Michael J
Blackman
Stefania Butini
Stefania
Butini
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
The Francis Crick Institute
2020
Difluorostatone-based inhibitors
Homology modeling
Malaria
Molecular docking
Pharmacophore modeling
Subtilisin-like protease
Amino Acid Sequence
Antimalarials
Binding Sites
Computer Simulation
Enzyme Inhibitors
Ligands
Models, Molecular
Molecular Conformation
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Sequence Data
Plasmodium
Protein Binding
Protozoan Proteins
Quantitative Structure-Activity Relationship
Sequence Alignment
Subtilisins
Blackman FC001043
0307 Theoretical and Computational Chemistry
0601 Biochemistry and Cell Biology
0803 Computer Software
Biophysics
Medicinal & Biomolecular Chemistry
2020-07-15 10:02:37
Journal contribution
https://crick.figshare.com/articles/journal_contribution/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/12607946
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 structure-based pharmacophore models that were combined in an inclusive pan-SUB1 pharmacophore (SUB1-PHA). This latter was validated by applying in silico methods, showing that it may be useful for the future development of potent antimalarial agents.