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.
Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Fazlin
F
Mohd Fauzi
Alexios
A
Koutsoukas
Robert
R
Lowe
Kalpana
K
Joshi
Tai-Ping
TP
Fan
Robert C
RC
Glen
Andreas
A
Bender
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects; D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology; D001185:Artificial Intelligence; D003198:Computer Simulation; D030541:Databases, Genetic; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008515:Medicine, Ayurvedic; D008516:Medicine, Chinese Traditional; D010946:Plants, Medicinal / Q000737:chemistry / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D051269:Sodium-Glucose Transporter 1 / Q000187:drug effects; D051297:Sodium-Glucose Transporter 2 / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; C473772:GPBAR1 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D017027:Protein Tyrosine Phosphatases