Structure-Based Design, Synthesis, and Characterization of Inhibitors of Human and Plasmodium falciparum Dihydroorotate Dehydrogenases

Abstract

Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUT-LeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.

Identification and Validation of Novel Drug Targets for the Treatment of Plasmodium falciparum Malaria: New Insights

“…These differences make PfDHODH a potential species-specific drug target [24], which was extensively explored by a considerable number of studies. Although early research have not yielded effective results, the following studies have led to important achievements in the discovery of PfDHODH inhibitors, such as benzimidazolyl thiophene-2-carboxamides [54][55][56], s-benzyltriazolopyrimidines [57], N-substituted salicylamides [58], trifluoromethyl phenyl butenamide derivatives [59], and triazolopyrimidine-based inhibitors [25,[60][61][62][63][64]. The triazolopyrimidine-based compound DSM265 was shown to be a potent inhibitor of the PfDHODH and Plasmodium vivax DHODH (PvDHODH) with excellent selectivity versus hDHODH [48].…”

Discovery of Biphenylacetamide-Derived Inhibitors of BACE1 Using de Novo Structure-Based Molecular Design

“…20 Since the terminal ring of the biaryl system of inhibitor 1 was docked into a hydrophobic site near…”

“…These fragments are then joined together in ways dictated by the user to yield synthetically approachable ligand scaffolds which are predicted to show good affinity for the target enzyme. [19][20][21] Here, we present the studies of a new BACE1 inhibitor scaffold designed using the de novo molecular design program SPROUT. 22,23 A library of structural analogs of the initial designed skeleton was synthesized and tested against recombinant BACE1.…”

Road Towards New Antimalarials – Overview of the Strategies and their Chemical Progress

“…Inhibitors of human DHODH are used for the treatment of rheumatoid arthritis, indicating that DHODH is a druggable target and small molecules such as 1 can be developed to inhibit DHODH. For example, enzymatic assays have revealed that 1 has very little activity against PfDHODH, which opens up the possibility for a species specific inhibitor [7]. X-ray studies of small molecules bound to DHODH have shown that the inhibitors occupy *Address correspondence to this author at the Genomics Institute of Novartis Research Foundation, 10675 John Jay Hopkins Dr., San Diego, CA 92121 USA; Tel: + 1 858 332 4751; Fax: +1 858 812 1648; E-mail: akc@gnf.org species variable pocket next to flavin cofactor providing the structural basis for species specificity [8][9][10].…”