Journal of Drug Design and Medicinal Chemistry

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In silico Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of Plasmodium falciparum M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile

Received: 17 November 2017    Accepted: 08 December 2017    Published: 11 January 2018
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Abstract

We virtually design here new subnanomolar range antimalarials, inhibitors of plasmodium falciparum M17 Aminopeptidase (pfA-M17), by means of structure-based molecular design. Complexation QSAR models were elaborated for two training sets (6 methylphosphonic acids (APP) resp. 13 Hydroxamic Acid derivatives (AHO): QSARAPP. resp. QSARAHO) and a linear correlation was established between the computed Gibbs free energies of binding (GFE: DDGcom) and observed enzyme inhibition constants (Kiexp) for each training set: QSARAPP: pKiexp=−0.1665´DDGcom+7.9581, R2=0.97 resp. QSARAHO: pKiexp=−0.4626´DDGcom+8.1842, R2=0.98. The predictive power of the QSAR models was validated with 3D-QSAR pharmacophore generation (PH4): PH4APP: pKiexp=0.99677´pKipred– 0.00457, R2=0.99 resp. PH4AHO: pKiexp =1.02016´pKipred–0.10478, R2=0.99. Breakdown of computed pfA-M17:APPs resp. pfA-M17:AHOs interaction energy into each active site residue’s contribution provided additional helpful structural information to design new APP and AHO analogues in a consistent way. In a first step we designed a virtual library (VLAPP resp. VLAHO) from P1 and P’ 1 substitutions to explore both S1 and S’ 1 pockets. Further the VLs screened with the 3D-QSAR PH4s and the Kipred of the best fit hits virtually evaluated with QSARAPP resp. QSARAHO models. This approach combining use of molecular modeling, PH4 and in silico VL screening helpfully provided valuable structural information for the synthesis of novel pfA-M17 inhibitors.

DOI 10.11648/j.jddmc.20170306.13
Published in Journal of Drug Design and Medicinal Chemistry (Volume 3, Issue 6, December 2017)
Page(s) 86-113
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Drug Design, QSAR Model, Pharmacophore Model, ADME Properties, Complexation Model, Molecular Modelling

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Author Information
  • Faculty of Fundamental and Applied Sciences (UFR SFA), Laboratoire de Physique Fondamentale et Appliquée, University Abobo Adjamé (Now Nangui Abrogoua), Abidjan, Cote D’Ivoire

  • Faculty of Fundamental and Applied Sciences (UFR SFA), Laboratoire de Physique Fondamentale et Appliquée, University Abobo Adjamé (Now Nangui Abrogoua), Abidjan, Cote D’Ivoire; International Centre for Science and High Technology (ICS-UNIDO), Area Science Park, Trieste, Italy

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    Hermann N'Guessan, Eugene Megnassan. (2018). In silico Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of Plasmodium falciparum M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile. Journal of Drug Design and Medicinal Chemistry, 3(6), 86-113. https://doi.org/10.11648/j.jddmc.20170306.13

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    Hermann N'Guessan; Eugene Megnassan. In silico Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of Plasmodium falciparum M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile. J. Drug Des. Med. Chem. 2018, 3(6), 86-113. doi: 10.11648/j.jddmc.20170306.13

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    AMA Style

    Hermann N'Guessan, Eugene Megnassan. In silico Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of Plasmodium falciparum M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile. J Drug Des Med Chem. 2018;3(6):86-113. doi: 10.11648/j.jddmc.20170306.13

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  • @article{10.11648/j.jddmc.20170306.13,
      author = {Hermann N'Guessan and Eugene Megnassan},
      title = {In silico Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of Plasmodium falciparum M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile},
      journal = {Journal of Drug Design and Medicinal Chemistry},
      volume = {3},
      number = {6},
      pages = {86-113},
      doi = {10.11648/j.jddmc.20170306.13},
      url = {https://doi.org/10.11648/j.jddmc.20170306.13},
      eprint = {https://download.sciencepg.com/pdf/10.11648.j.jddmc.20170306.13},
      abstract = {We virtually design here new subnanomolar range antimalarials, inhibitors of plasmodium falciparum M17 Aminopeptidase (pfA-M17), by means of structure-based molecular design. Complexation QSAR models were elaborated for two training sets (6 methylphosphonic acids (APP) resp. 13 Hydroxamic Acid derivatives (AHO): QSARAPP. resp. QSARAHO) and a linear correlation was established between the computed Gibbs free energies of binding (GFE: DDGcom) and observed enzyme inhibition constants (Kiexp) for each training set: QSARAPP: pKiexp=−0.1665´DDGcom+7.9581, R2=0.97 resp. QSARAHO: pKiexp=−0.4626´DDGcom+8.1842, R2=0.98. The predictive power of the QSAR models was validated with 3D-QSAR pharmacophore generation (PH4): PH4APP: pKiexp=0.99677´pKipred– 0.00457, R2=0.99 resp. PH4AHO: pKiexp =1.02016´pKipred–0.10478, R2=0.99. Breakdown of computed pfA-M17:APPs resp. pfA-M17:AHOs interaction energy into each active site residue’s contribution provided additional helpful structural information to design new APP and AHO analogues in a consistent way. In a first step we designed a virtual library (VLAPP resp. VLAHO) from P1 and P’ 1 substitutions to explore both S1 and S’ 1 pockets. Further the VLs screened with the 3D-QSAR PH4s and the Kipred of the best fit hits virtually evaluated with QSARAPP resp. QSARAHO models. This approach combining use of molecular modeling, PH4 and in silico VL screening helpfully provided valuable structural information for the synthesis of novel pfA-M17 inhibitors.},
     year = {2018}
    }
    

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  • TY  - JOUR
    T1  - In silico Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of Plasmodium falciparum M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile
    AU  - Hermann N'Guessan
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    AB  - We virtually design here new subnanomolar range antimalarials, inhibitors of plasmodium falciparum M17 Aminopeptidase (pfA-M17), by means of structure-based molecular design. Complexation QSAR models were elaborated for two training sets (6 methylphosphonic acids (APP) resp. 13 Hydroxamic Acid derivatives (AHO): QSARAPP. resp. QSARAHO) and a linear correlation was established between the computed Gibbs free energies of binding (GFE: DDGcom) and observed enzyme inhibition constants (Kiexp) for each training set: QSARAPP: pKiexp=−0.1665´DDGcom+7.9581, R2=0.97 resp. QSARAHO: pKiexp=−0.4626´DDGcom+8.1842, R2=0.98. The predictive power of the QSAR models was validated with 3D-QSAR pharmacophore generation (PH4): PH4APP: pKiexp=0.99677´pKipred– 0.00457, R2=0.99 resp. PH4AHO: pKiexp =1.02016´pKipred–0.10478, R2=0.99. Breakdown of computed pfA-M17:APPs resp. pfA-M17:AHOs interaction energy into each active site residue’s contribution provided additional helpful structural information to design new APP and AHO analogues in a consistent way. In a first step we designed a virtual library (VLAPP resp. VLAHO) from P1 and P’ 1 substitutions to explore both S1 and S’ 1 pockets. Further the VLs screened with the 3D-QSAR PH4s and the Kipred of the best fit hits virtually evaluated with QSARAPP resp. QSARAHO models. This approach combining use of molecular modeling, PH4 and in silico VL screening helpfully provided valuable structural information for the synthesis of novel pfA-M17 inhibitors.
    VL  - 3
    IS  - 6
    ER  - 

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