Authors
R L van Zyl1; P Agarwal1; C J van der Westhuizen2; J L Panayides2; 1 Pharmacology Division; WITS Research Institute for Malaria (WRIM); Faculty of Health Sciences; University of the Witwatersrand, South Africa; 2 Pharmaceutical Technologies, Future Production: Chemicals, Council for Scientific and Industrial Research (CSIR), South Africa Discussion
Atovaquone is a clinically used antimalarial drug that inhibits the cytochrome bc1 complex of the malaria parasite, but the parasite is rapidly developing resistance against this target site. Thus, there is a need to develop new drugs that will overcome the resistance and retain a favourable pharmacokinetic profile. This study assessed the effect of 30 different naphthoquinone compounds (including atovaquone) on the Plasmodium falciparum cytochrome bc1 complex using various computational models. These compounds were evaluated against cytochrome bc1 complex (PDB 4PD4) to compare the docking scores with atovaquone. Modelling was done using the Schrödinger software suite to evaluate the naphthoquinone compounds using Glide XP, Prime MM-GBSA and QikProp. Docking studies revealed that NPHQ-4, NPHQ-16, NPHQ-15 and NPHQ-18 possessed docking scores of -12.26, -11.70, -11.62 and -11.37 kcal/mol, respectively; which were higher than atovaquone (-11.22 kcal/mol). Prime MM-GBSA analysis yielded the relative binding energies (MMGBSA_dG_Bind) of NPHQ-4, NPHQ-16, NPHQ-15, NPHQ-18 and atovaquone with -57.23, -56.33, -65.95, -56.63 and -51.30 kcal/mol, respectively. These results suggest that select compounds bind to the target site more strongly than atovaquone. QikProp analysis indicated atovaquone, NPHQ-4, NPHQ-16 and NPHQ-18 complied with all Lipinski Rule of 5 “drug-like” properties. Whilst NPHQ-15 did not comply with 2 rules, contributing to a 94.5% predicted oral absorption compared to 100% for atovaquone and being too polar to cross the blood brain barrier. Swiss-ADME drug-likeliness analysis indicated that NPHQ-4 and NPHQ-16 spossesed favourable properties, whilst NPHQ-18 did not comply with 1 rule. Preliminary data indicated that NPHQ-4, NPHQ-16 and NPHQ-18 have the potential to serve as lead antimalarial compounds for designing inhibitors of the cytochrome bc1 complex. Although NPHQ-17, NPHQ-14 and NPHQ-8 showed lower docking score compared to atovaquone, their predicted relative binding energies were higher. When analysed for drug-likeliness, NPHQ-14 and NPHQ-17 did not comply with 1 of Lipinski’s rule of 5. These compounds have indicated key structural features required to design more target-specific inhibitors. 
