Volume 3, Issue 6, December 2017, Page: 86-113
In silico Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of Plasmodium falciparum M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile
Hermann N'Guessan, Faculty of Fundamental and Applied Sciences (UFR SFA), Laboratoire de Physique Fondamentale et Appliquée, University Abobo Adjamé (Now Nangui Abrogoua), Abidjan, Cote D’Ivoire
Eugene Megnassan, 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
Received: Nov. 17, 2017;       Accepted: Dec. 8, 2017;       Published: Jan. 11, 2018
DOI: 10.11648/j.jddmc.20170306.13      View  1699      Downloads  114
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.
Keywords
Drug Design, QSAR Model, Pharmacophore Model, ADME Properties, Complexation Model, Molecular Modelling
To cite this article
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, Journal of Drug Design and Medicinal Chemistry. Vol. 3, No. 6, 2017, pp. 86-113. doi: 10.11648/j.jddmc.20170306.13
Copyright
Copyright © 2017 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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