Physics-based simulations applied to macromolecules: Plasmodium falciparum Dihydroorotate Dehydrogenase (6 VTY) in complexation with a series of pyrrole-derived inhibitors

Despite the efforts and resources devoted to combating malaria, as well as the knowledge acquired about the different species of Plasmodium, of which Plasmodium falciparum is the most common in humans, malaria remains the leading endemic parasitic disease in the world. Malaria alone is responsible for approximately 597,000 deaths. It mainly affects pregnant women and children under the age of 5. The emergence of drug-resistant strains of the parasite poses a major challenge in the treatment of malaria. The enzyme dihydroorotate dehydrogenase (DHODH, pdb code: 6VTY) plays a crucial role in the treatment of malaria through the pyrimidine biosynthesis pathway, which is essential for the growth and reproduction of the Plasmodium falciparum (pf) parasite. Physics-based simulations applied to macromolecules are a major asset in the development of new drugs capable of overcoming resistance issues, improving selectivity, and increasing clinical efficacy. Using structure-based molecular design, we have developed Quantitative Structure-Activity Relationship (QSAR) models of 3D complexation from pyrrole (Pyl) molecule derivatives. A linear correlation has been established between Gibbs free energies (GFE:) and the observed enzyme inhibition constants (  for each complex formed: = - 0.1207×+ 7.8526; R² = 0.95. The effect of the biological (aqueous) environment was taken into account as a component of through the free energy of molecular electrostatic solvation  solution of the Poisson-Boltzmann equation. The predictive power of the RQSA model was validated by the generation of 3D-RQSA Pharmacophores (PH4): = 1,1585×1.1448; R² = 0.93. The combination of 3D complexation and 3D-RQSA pharmacophore methodologies has provided key insights into the orientation and configuration of pyrrole (Pyl) molecules within the active site of dihydroorotate dehydrogenase (DHODH) for effective malaria control.