Physicochemical Profiling and Comparison of Research Antiplasmodials and Advanced Stage Antimalarials with Oral Drugs.

Abstract

To understand the property space of antimalarials, we collated a large dataset of research antiplasmodial (RAP) molecules with known in vitro potencies and advanced stage antimalarials (ASAMs) with established oral bioavailability. While RAP molecules are “non-druglike”, ASAM molecules display properties closer to Lipinski’s and Veber’s thresholds. Comparison within the different potency groups of RAP molecules indicates that the in vitro potency is positively correlated to the molecular weight, the calculated octanol–water partition coefficient (clog P), aromatic ring counts (#Ar), and hydrogen bond acceptors. Despite both categories being bioavailable, the ASAM molecules are relatively larger and more lipophilic, have a lower polar surface area, and possess a higher count of heteroaromatic rings than oral drugs. Also, antimalarials are found to have a higher proportion of aromatic (#ArN) and basic nitrogen (#BaN) counts, features implicitly used in the design of antimalarial molecules but not well studied hitherto. We also propose using descriptors scaled by the sum of #ArN and #BaN (SBAN) to define an antimalarial property space. Together, these results may have important applications in the identification and optimization of future antimalarials.