Drug to Genome to Drug: Discovery of New Antiplasmodial Compounds

Abstract

The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum . However, it appears that screening directly on the parasite is a more rewarding approach. The "drug to genome to drug" approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum.

Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

“…From these analyses potential template proteins were identified and additional criteria were examined to select the most appropriate crystal structure for homology modelling purposes. Compounds De Ninno 1 and De Ninno 14 were taken from the study by De Ninno and coworkers [31] while compound Beghyn 10 was taken from the research recently described by Beghyn et al [22], and in each case utilises their numbering schemes Model building and minimisation Each homology model was generated using Prime version 2.2 (Maestro version 9.1, Schrödinger, LLC, New York, USA) employing the optimised sequence alignment. The model building process used the PDE9A structure 3DYN [29] and retained the endogenous cGMP ligand, metal ions together with their coordinated water molecules.…”

“…Very recently, Beghyn et al [22] implemented a 'drug to genome to drug' approach to design and test a series of PfPDE inhibitors based on tadalafil. Docking of compound 10 from the Beghyn study [22] (Fig.…”

“…Prior studies on the PfPDE biochemistry of zaprinast [32] and tadalafil analogues [22], as well as the docking of the hPDE9A and hPDE1 selective inhibitors described above show the potential for developing PfPDE inhibitors from hPDE ligands. An important further element is the need to remove hPDE potency while retaining PfPDE potency to achieve selectivity for the malarial PDEs.…”

“…In a similar manner, targeting residues identified as being unique to PfPDEb, c and d ( Table 2) may offer a means by which selectivity toward each isozyme may be achieved. Beghyn and co-workers [22] designed a set of tadalafil analogues where the N-methyl group was replaced with benzyl substituted pyrrolidine or Hydrogen bonds are shown with dashed lines. Purine-scanning glutamine and purine-stacking phenylalanine residues are highlighted, as well as residues unique to PfPDEa (A-E) Fig.…”

“…Interestingly, zaprinast was able to inhibit PfPDEa with an IC 50 of 3.8 lM and to inhibit parasite proliferation with an EC 50 of 35 lM [21]. More recently, Beghyn and co-workers [22] developed a series of tadalafil analogues as potential inhibitors of PfPDEs with the best compound ( Fig. 2) showing potent antiplasmodial activity (IC 50 0.5 lM).…”