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.
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