A structural comparative approach to identifying novel antimalarial inhibitors

• We have used a computational structural comparative approach to identify compounds that can selectively target an essential malaria protein.
• We have used AutoDock Vina to compare the binding affinities of potential inhibitors against an essential enzyme in Plasmodium falciparum and its human homolog.
• We were able to identify two inhibitors of P. falciparum in the ng/mL range.

Malaria continues to affect millions of people annually. With the rise of drug resistant strains, the need for alternative treatments has become increasingly urgent. Recently, PfUCHL3 was identified as an essential deubiquitinating enzyme. The increasing number of drug target structures being solved has increased the feasibility of utilizing a structural comparative approach to identifying novel inhibitors. Using AutoDock Vina, we recently screened the NCI library of about 320,000 compounds against the crystal structure of PfUCHL3. The top hits were subsequently screened against its human ortholog UCHL3 as to identify compounds that could specifically target the PfUCHL3 over its human counterpart. This method was used to identify small molecule inhibitors that can preferentially inhibit the parasitic enzyme. Several compounds were identified that demonstrated significant binding affinity preference for the malaria target over the human enzyme. Two of these compounds demonstrated ng/mL activity.

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