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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.

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Title: 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.
Authors: Brogi, Simone1,2,3, Giovani, Simone1,2,3, Brindisi, Margherita1,2,3, Gemma, Sandra1,2,3 gemma@unisi.it, Novellino, Ettore1,4, Campiani, Giuseppe1,2,3 campiani@unisi.it, Blackman, Michael J.5, Butini, Stefania1,2,3
Source: Journal of Molecular Graphics & Modelling. Mar2016, Vol. 64, p121-130. 10p.
Subjects: Plasmodium falciparum, Protease inhibitors, Subtilisins, Antimalarials, Molecular docking
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 ((4 S )-( N -(( N -acetyl- l -lysyl)- l -isoleucyl- l -threonyl- l -alanyl)-2,2-difluoro-3-oxo-4-aminopentanoyl)glycine ( 1 ) and (4 S )-( 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. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Molecular Graphics & Modelling is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
An: 113216181
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PubType: Academic Journal
PubTypeId: academicJournal
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  Data: 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.
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  Data: <searchLink fieldCode="AR" term="%22Brogi%2C+Simone%22">Brogi, Simone</searchLink><relatesTo>1,2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Giovani%2C+Simone%22">Giovani, Simone</searchLink><relatesTo>1,2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Brindisi%2C+Margherita%22">Brindisi, Margherita</searchLink><relatesTo>1,2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Gemma%2C+Sandra%22">Gemma, Sandra</searchLink><relatesTo>1,2,3</relatesTo><i> gemma@unisi.it</i><br /><searchLink fieldCode="AR" term="%22Novellino%2C+Ettore%22">Novellino, Ettore</searchLink><relatesTo>1,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Campiani%2C+Giuseppe%22">Campiani, Giuseppe</searchLink><relatesTo>1,2,3</relatesTo><i> campiani@unisi.it</i><br /><searchLink fieldCode="AR" term="%22Blackman%2C+Michael+J%2E%22">Blackman, Michael J.</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Butini%2C+Stefania%22">Butini, Stefania</searchLink><relatesTo>1,2,3</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Molecular+Graphics+%26+Modelling%22">Journal of Molecular Graphics & Modelling</searchLink>. Mar2016, Vol. 64, p121-130. 10p.
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  Data: <searchLink fieldCode="DE" term="%22Plasmodium+falciparum%22">Plasmodium falciparum</searchLink><br /><searchLink fieldCode="DE" term="%22Protease+inhibitors%22">Protease inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Subtilisins%22">Subtilisins</searchLink><br /><searchLink fieldCode="DE" term="%22Antimalarials%22">Antimalarials</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+docking%22">Molecular docking</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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 ((4 S )-( N -(( N -acetyl- l -lysyl)- l -isoleucyl- l -threonyl- l -alanyl)-2,2-difluoro-3-oxo-4-aminopentanoyl)glycine ( 1 ) and (4 S )-( 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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Molecular Graphics & Modelling is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1016/j.jmgm.2016.01.005
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      – Code: eng
        Text: English
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        PageCount: 10
        StartPage: 121
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      – SubjectFull: Plasmodium falciparum
        Type: general
      – SubjectFull: Protease inhibitors
        Type: general
      – SubjectFull: Subtilisins
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      – SubjectFull: Antimalarials
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      – SubjectFull: Molecular docking
        Type: general
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      – TitleFull: 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.
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            NameFull: Brogi, Simone
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              Text: Mar2016
              Type: published
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