Chemogenomics Approaches to Rationalizing the Mode-of-Action of Traditional Chinese and Ayurvedic Medicines

Traditional Chinese medicine (TCM) and Ayurveda have
been used
in humans for thousands of years. While the link to a particular indication
has been established in man, the mode-of-action (MOA) of the formulations
often remains unknown. In this study, we aim to understand the MOA
of formulations used in traditional medicine using an in silico target prediction algorithm, which aims to predict protein targets
(and hence MOAs), given the chemical structure of a compound. Following
this approach we were able to establish several links between suggested
MOAs and experimental evidence. In particular, compounds from the
’tonifying and replenishing medicinal’ class from TCM
exhibit a hypoglycemic effect which can be related to activity of
the ingredients against the Sodium-Glucose Transporters (SGLT) 1 and
2 as well as Protein Tyrosine Phosphatase (PTP). Similar results were
obtained for Ayurvedic anticancer drugs. Here, both primary anticancer
targets (those directly involved in cancer pathogenesis) such as steroid-5-alpha-reductase
1 and 2 were predicted as well as targets which act synergistically
with the primary target, such as the efflux pump P-glycoprotein (P-gp).
In addition, we were able to elucidate some targets which may point
us to novel MOAs as well as explain side effects. Most notably, GPBAR1,
which was predicted as a target for both ’tonifying and replenishing
medicinal’ and anticancer classes, suggests an influence of
the compounds on metabolism. Understanding the MOA of these compounds
is beneficial as it provides a resource for NMEs with possibly higher
efficacy in the clinic than those identified by single-target biochemical
assays.