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Understanding the structural requirements in diverse scaffolds for the inhibition of P. falciparum dihydroorotate dehydrogenase (PfDHODH) using 2D-QSAR, 3D-pharmacophore and structure-based energy- optimized pharmacophore models.

P. falciparum dihydroorotate dehydrogenase (PfDHODH) of the pyrimidine biosynthetic pathway offers a promising target for the development of antimalarial drugs in the scenario of widespread P. falciparum resistance. In this background, we have made an effort to decipher the structural requirements for the inhibition of PfDHODH using regression-based 2DQSAR, 3D-pharmacophore modeling and energy-based pharmacophoric (e-pharmacophore) studies. The 2D-QSAR and 3D-pharmacophore models were built from a structurally diverse set of 38 dihydrothiophenone derivatives, while the e-pharmacophore models were developed from two different co-crystal structures (PDB ID: 3O8A, 3I68) with varied scaffolds (benzimidazole, IC50: 22 nM and triazolopyrimidine, IC50: 56 nM) showing an inhibitory activity against the PfDHODH. The 2D-QSAR modeling study depicted the contribution of constitutional (number of oxygen atoms), spatial (molar volume), structural (number of rotatable bonds), and electronic (dipole moment) descriptors in predicting the PfDHODH inhibitory activity. The regression model showed the maximum contribution of constitutional descriptor (number of oxygen atoms representing the hydrogen bond acceptor feature) in determining the inhibitory activity. The best 3D-pharmacophore model (Hypo-1) with a correlation coefficient of 0.960 showed two hydrogen bond acceptor (HBA) and one ring aromatic (RA) features as the essential structural requirements for predicting the inhibitory activity. The e-pharmacophores derived from two different co-crystal structures highlighted the energy-based contribution of one hydrogen bond acceptor (e-HBA), one hydrogen bond donor (e-HBD) and three/four ring aromatic (e-RA) features for the inhibitory activity. The screening of external sets by the e-pharmacophores showed that both the models are capable of identifying the structurally diverse and potent compounds.