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 contributionposted on 2020-07-15, 10:02 authored by Simone Brogi, Simone Giovani, Margherita Brindisi, Sandra Gemma, Ettore Novellino, Giuseppe Campiani, Michael J Blackman, Stefania Butini
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.
Difluorostatone-based inhibitorsHomology modelingMalariaMolecular dockingPharmacophore modelingSubtilisin-like proteaseAmino Acid SequenceAntimalarialsBinding SitesComputer SimulationEnzyme InhibitorsLigandsModels, MolecularMolecular ConformationMolecular Docking SimulationMolecular Dynamics SimulationMolecular Sequence DataPlasmodiumProtein BindingProtozoan ProteinsQuantitative Structure-Activity RelationshipSequence AlignmentSubtilisinsBlackman FC0010430307 Theoretical and Computational Chemistry0601 Biochemistry and Cell Biology0803 Computer SoftwareBiophysicsMedicinal & Biomolecular Chemistry