Abstract
We virtually design here new subnanomolar range antimalarials, inhibitors of <i>plasmodium falciparum</i> M17 Aminopeptidase (<i>pf</i>A-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): QSAR<sub>APP</sub>. resp. QSAR<sub>AHO</sub>) and a linear correlation was established between the computed Gibbs free energies of binding (GFE: DDG<sub>com</sub>) and observed enzyme inhibition constants (K<sub>i</sub><sup>exp</sup>) for each training set: QSAR<sub>APP</sub>: pK<sub>i</sub><sup>exp</sup>=−0.1665´DDG<sub>com</sub>+7.9581, R<sup>2</sup>=0.97 resp. QSAR<sub>AHO</sub>: pK<sub>i</sub><sup>exp</sup>=−0.4626´DDG<sub>com</sub>+8.1842, R<sup>2</sup>=0.98. The predictive power of the QSAR models was validated with 3D-QSAR pharmacophore generation (PH4): PH4<sub>APP</sub>: pK<sub>i</sub><sup>exp</sup>=0.99677´pK<sub>i</sub><sup>pred</sup>– 0.00457, R<sup>2</sup>=0.99 resp. PH4<sub>AHO</sub>: pK<sub>i</sub><sup>exp</sup> =1.02016´pK<sub>i</sub><sup>pred</sup>–0.10478, R<sup>2</sup>=0.99. Breakdown of computed <i>pf</i>A-M17:APPs resp. <i>pf</i>A-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 (VL<sub>APP</sub> resp. VL<sub>AHO</sub>) from P<sub>1</sub> and P’ <sub>1</sub> substitutions to explore both S<sub>1</sub> and S’ <sub>1</sub> pockets. Further the VLs screened with the 3D-QSAR PH4s and the K<sub>i</sub><sup>pred</sup> of the best fit hits virtually evaluated with QSAR<sub>APP</sub> resp. QSAR<sub>AHO</sub> models. This approach combining use of molecular modeling, PH4 and <i>in silico</i> VL screening helpfully provided valuable structural information for the synthesis of novel pfA-M17 inhibitors.
Highlights
Malaria, along with tuberculosis and HIV/AIDS are the major infectious diseases infecting hundred millions people each year at such a level that the United Nations raised their eradication as a Millennium Development Goal (MDG 6: “Combat HIV/AIDS, malaria and other diseases”)
In this regard the breakdown of interaction energy to each active site residue contribution clearly ordered the pockets S1’ >> S1 when comparing their affinity with APP1 and AHO1: a key information (Table 9) which directed our effort to design an initial diversity virtual combinatorial library of new analogues to be screened by the pharmacophore models derived from the Gibbs free energies of binding (GFE) QSAR
The initial library filtered by a set of ADME-related descriptors to a focused one subsequently was screened by mapping of the analogues to the PH4AHO
Summary
Along with tuberculosis and HIV/AIDS are the major infectious diseases infecting hundred millions people each year at such a level that the United Nations raised their eradication as a Millennium Development Goal (MDG 6: “Combat HIV/AIDS, malaria and other diseases”). One alternative to ACT anti pf resistance strategy is the design of hybrid drugs where two antimalarial moieties are linked into a unique molecule, these moieties known for their confirmed antimalarial potency against two different parasite targets and operating according different mechanisms of action [4, 5, 6]. Another promising gate was opened through the identification and characterization of new parasite therapeutic targets such as metalloaminopeptidases (MAP), reported to play a crucial role in the parasite viability and survival [7, 8, 9]. Among them both M1 alanyl and M17 leucyl specific aminopeptidases (pfA-M1, pfA-M17) are validated ones, due to their mediation during the final stage of hemoglobin digestion were they split small peptide fragments into free amino acids and thereafter by their inhibition which is lethal to pf [10, 11] they are worth targeting
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