Protein kinases as potential drug targets for new antimalarial drugs

Introduction: Malaria is one of the most prevalent infectious diseases in the world, accounting for over 500,000 deaths annually worldwide. In absence of an effective vaccine, rapid treatment is vital for effective malaria control. However, among the greatest challenges in battling malaria is the recurrent emergence and spread of parasite resistance to antimalarial drugs. Protein kinases are one of the classes of proteins that have been explored as potential targets for new antimalarial drugs. As such, the goal of this study was to identify P. vivax kinases that may represent potential drug targets in asexual blood stages of the parasite life cycle. Materials and Methods: We searched for protein kinases in the P. vivax genome using the target search tool from the TDR Targets database. The protein kinase domain was identified using the Pfam (E-value < 10-10) database. Information about essentiality of each kinase for P. vivax asexual blood stages was retrieved from the data available for orthologs of P. falciparum and P. berghei. Predicted P. vivax targets were aligned with human protein kinases using pairwise BLAST. Results: We found 66 proteins with kinase domains in the P. vivax genome. Of these, 45 (68%) are predicted to be essential for asexual blood stages. Pairwise sequence alignment was used to identify conserved protein kinases between Plasmodium species (>90% identity) that present low identity (<45%) with human kinases, which can be useful to help find selective parasite kinase inhibitors. Using these criteria, we selected six kinases as candidate targets (PvARK1, PvCDPK1, PvNEK1, PvPKG, PVX_092985, and PVX_092865). To date, crystal structure is available only for PvPKG (PDB: 5FET) and this structure was used for a virtual screening by docking kinase inhibitors of two subsets from Chembridge (~22.000 compounds) using Glide software. Several compounds showed predicted Ki values against PvPKG in the nanomolar range. Conclusion: Using in silico approaches, we identified protein kinases as potential drug targets in P. vivax. Based on a structure-based virtual screening, we identified compounds with predicted activity in the nanomolar range against an essential parasite kinase s (PKG). The antimalarial activity of these compounds is currently under investigation. Financial support: FAPESP (grant number 2012/ 16525-2 and fellowship 2015/ 20774-6).