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

Abstract

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): QSAR APP . resp. QSAR AHO ) and a linear correlation was established between the computed Gibbs free energies of binding (GFE: ∆∆G com ) and observed enzyme inhibition constants (K i exp ) for each training set: QSAR APP : pK i exp =−0.1665×∆∆G com +7.9581, R 2 =0.97 resp. QSAR AHO : pK i exp =−0.4626×∆∆G com +8.1842, R 2 =0.98. The predictive power of the QSAR models was validated with 3D-QSAR pharmacophore generation (PH4): PH4 APP : pK i exp =0.99677×pK i pred -0.00457, R 2 =0.99 resp. PH4 AHO : pK i exp =1.02016×pK i pred -0.10478, R 2 =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 (VL APP resp. VL AHO ) from P 1 and P' 1 substitutions to explore both S 1 and S' 1 pockets. Further the VLs screened with the 3D-QSAR PH4s and the K i pred of the best fit hits virtually evaluated with QSAR APP resp. QSAR AHO 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.

Structure-Based Design and in Silico Screening of Virtual Combinatorial Library of Benzamides Inhibiting 2-trans Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Predicted Pharmacokinetic Profiles

“…In silico screening of a virtual (combinatorial) library can lead to hit identification as it was shown in our previous works on inhibitors design [17,28,29].…”

Computer-Aided Design of Peptidomimetic Inhibitors of Falcipain-3: QSAR and Pharmacophore Models

“…3D models of the enzyme-inhibitor (E:I) complexes were built starting from the free enzyme (E) and the free inhibitors (I), both derived from a well -refined X-ray crystal structure (PDB ID: 3BWK) of the co-crystallised potent inhibitor K11017 (or Mu-Leu-Hph-VSPh, where VSPh: phenyl vinyl sulfone; Hph:homophenylalanyl;Mu:morpholino urea) retrieved from the PDB [32]. Chain A was employed in all computations and modellingwas carried out on the graphical user in-terface of Discovery Studio 2.5 [33], using a previously well described protocol [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. Thus, the pH values were kept at 7.0, while all N-and C-terminal residues were kept neutral.…”

“…Such an approach could reduce the required number of molecules to be synthesised in a rational drug development project quite considerably. The above procedure has been previously applied by our team in several drug design projects [34,36,[38][39][40][41][42][43][44][45][46][47].…”

Computer-aided Design of Peptidomimetic Inhibitors of falcipain-3: QSAR and Pharmacophore Models

“…3D models of the enzyme-inhibitor (E:I) complexes were built starting from the free enzyme (E) and the free inhibitors (I), both derived from a well -refined X-ray crystal structure (PDB ID: 3BWK) of the co-crystallised potent inhibitor K11017 (or Mu-Leu-Hph-VSPh where VSPh: phenyl vinyl sulfone; Hph: homophenylalanyl; Mu: morpholino urea) retrieved from the PDB [31]. Chain A was employed in all computations and modeling done on the graphical user interface of Discovery Studio 2.5 [32], using a previously well described protocol [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. This implies that the pH values were kept at 7.0, while all N-and C-terminal residues were kept neutral, while all water molecules originally in the crystal structure were deleted and protonated and ionized amino acid residues were charged.…”

“…Such an approach could reduce the required number of molecules to be synthesized in a rational drug development project quite considerably. The above procedure has been previously applied by our team in several drug design projects [33,35,[37][38][39][40][41][42][43][44][45][46].…”