In silico identification of novel inhibitors against Plasmodium falciparum dihydroorate dehydrogenase.
Plasmodium falciparum causes the most fatal form of malaria and accounts for over 1 million deaths annually, yet currently used drug therapies are compromised by resistance. The malaria parasite cannot salvage pyrimidines and relies on de novo biosynthesis for survival. The enzyme dihydrooratate dehydrogenase (DHODH), a mitochondrial flavoenzyme, catalyzes the rate-limiting step of this pathway and is therefore an attractive anti-malarial chemotherapeutic target. In an effort to design new and potential anti-malarials, structure-based pharmacophore mapping, molecular docking, binding energy calculations and binding affinity predictions were employed in a virtual screening strategy to design new and potent P. falciparum dihydrooratate dehydrogenase (PfDHODH) inhibitors. A structure-based pharmacophore model was generated which consist of important interactions as observed in co-crystal of PfDHODH enzyme. The developed model was used to retrieve molecules from ChemBridge database, a freely available commercial database. A total of 87 molecules mapped on the modeled pharmacophore from the database. The retrieved hits were further screened by docking simulation, binding energy calculations and biding affinity predictions using genetic optimization for ligand docking (GOLD) and MOE. Based on these results, finally 26 chemo-types molecules were predicted as new, potential and structurally diverse PfDHODH inhibitors.
Department of Biochemistry, University College of Science, Shankar, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan. awadood@awkum.edu.pk
Abdul
A
Wadood
Zaheer-ulhaq
ZU
Ulhaq
D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors