Study by Molecular Docking of the Interactions between Dihydroorotate Dehydrogenase and a Series of Inhibitors of Pyrrole Derivatives for the treatment of Malaria

Abstract

Malaria, although a curable disease, continues to be the most important infectious disease in terms of incidence and mortality worldwide. It is a potentially fatal disease caused by parasites transmitted to people through the bites of infected female Anopheles mosquitoes. This disease affects more than 216 million people and kills a million, mainly children and pregnant women. Anti-malaria therapy finds itself confronted with drug-resistant strains, hence the urgency of finding new targets and new anti-infectious agents. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme for the design of new antimalarial drugs. Using a Computer Aided Molecular Design (CAMD) reaction approach, a series of 17 molecules from the pyrrole family, inhibitors of (DHODH) was designed within the protein (PDB code: 6VTN). These molecules with known \(IC_{50}\) were selected to build an RQSAR model presenting a linear correlation between the Gibbs energy (∆∆G), the complexes formed and the experimental inhibition potential (\(pIC_{50}^{exp}\))  : \(pIC_{50}^{exp}\) = - 0.2909 × ∆∆G + 7.7715 ; R2 = 0,97. we subsequently carried out a study on the catalytic residues (interaction by residue)  in order to exploit the different interactions (enzyme: inhibitor).The predictive power of the QSAR model was validated by the generation of 3D-QSAR pharmacophores (PH4): \(pIC_{50}^{exp}\) = 0.9939 x \(pIC_{50}^{est}\) + 0.0421 ; R2 = 0.92.