STRUCTURE-BASED DESIGN OF NOVEL PYRIMIDINE CARBONITRILES ANALOGS TARGETING THE CYSTEINE PROTEASE FALCIPAIN 2 OF PLASMODIUM FALCIPARUM (pfFP2) AT THE TROPHOZOÏTE STAGE WITH FAVORABLE ADME SPECIFICITIES

Yves Kily Hervé Fagnidi; Eric Ziki; Koffi N’Guessan Placide Gabin Allangba; Beguemsi Toï; Eugene Megnassan

doi:10.22270/ujpr.v8i5.1008

Yves Kily Hervé Fagnidi Department of Science and Technology, University Alassane Ouattara, Ivory Coast. Fundamental and Applied Physics Laboratory, University Nangui Abrogoua, Ivory Coast.
Eric Ziki Laboratory of Material Sciences, the Environment and Solar Energy, University Felix Houphouët-Boigny, Ivory Coast.
Koffi N’Guessan Placide Gabin Allangba Fundamental and Applied Physics Laboratory, University Nangui Abrogoua, Ivory Coast. Laboratory of Environmental Science and Technology, University Jean Lorougnon Guédé, Ivory Coast. Laboratory of Biophysics and Nuclear Medicine (LBNM), University Félix Houphouët-Boigny, Ivory Coast. Department of Medical Physics, University of Trieste, Trieste, Italy. 7Ecole Normale Supérieure, Abidjan, Ivory Coast. ICTP-UNESCO, QLS, Strada Costiera 11, I 34151 Trieste, Italy.
Beguemsi Toï Ecole Normale Supérieure, Abidjan, Ivory Coast. Laboratory of Structural and Theoretical Organic Chemistry, University Felix Houphouët Boigny, Ivory Coast.
Eugene Megnassan Fundamental and Applied Physics Laboratory, University Nangui Abrogoua, Ivory Coast. Laboratory of Structural and Theoretical Organic Chemistry, University Felix Houphouët Boigny, Ivory Coast. ICTP-UNESCO, QLS, Strada Costiera 11, I 34151 Trieste, Italy.

10.22270/ujpr.v8i5.1008

Keywords:

ADMET, CNP, FP2, Malaria, pharmacophore, QSAR, virtual screening

Abstract

Aim and Objective: Structure-based drug design (SBDD) of new antimalarials at the moment of resistance of the most causative agent, Plasmodium falciparum to the more valuable artemisinin combination therapy (ACT) is even more urgent. Carbonitriles pyrimidine derivatives (CNP) has emerged as potential inhibitors of the cysteine protease falcipain 2 of Plasmodium falciparum (pfFP2), so here we report virtual pharmacophore based screening of the CNP chemical subspace yielding novel CNP analogs with predicted high inhibitory potency against pfFP2.

Methods: A quantitative structure activity relationships (QSAR) complexation model has been developed from a series of fifteen carbonitriles pyrimidine derivatives to establish a linear correlation between the calculated Gibbs free energies (GFE: ΔΔG_com) of pfFP2-CNP complex formation and the experimental half-maximal enzymatic inhibition concentration ( ).The predictive power of the QSAR model was then validated with the generation of a 3D-QSAR-PH4 pharmacophore (PH4) model as CNP chemical subspace (exemplified as a virtual combinatorial library of more than 83.300 CNP analogs) explorer for novel predicted more potent CNP analogs. Finally the best PH4 hits were evaluated with the initial QSAR model for predicted potency ( ) and pharmacokinetic profile.

Results: The QSAR model linear correlation equation: p = -0.1025 x ∆∆G_com + 7.2867, R²=0.94, the subsequent PH4 model linear correlation between experiment and PH4-estimated IC₅₀: p = 0.9366 x p + 0.2849, R²=0.91 documents the high predictive power of this approach. Finally the screening of the virtual library of CNP analogs yielded 52 orally bioavailable candidates the best reaching a predicted potency ( ) of 14 pM and displaying favorable pharmacokinetic profile.

Conclusion: The combined use of one descriptor complexation QSAR model and 3D-QSAR Pharmacophore model performs well in identifying novel CNP analogs against pfFP2 and the handful of top predicted analogs are worth undergoing synthesis and biological evaluation.