Most drugs exert their effects through their combined action on several different molecular targets (polypharmacology). Rather than being contained in one organ or tissue, these targets exhibit various levels of espression throughout the human body. Thus, a drug designed to treat a specific condition can have unintended effects in bystander tissues and organs. Undiscovered biological effects of genes and drugs during the validation and testing stages thwarts investigative projects and slows pharmaceutical drug development and repurposing. The heart issues that derailed the blockbuster drug Vioxx is one such case of a surpise, tissue-specific adverse effect. (For more on the Vioxx example–and others–check out our blog.)
Surprisingly, before now, there were few or no tools for easily predicting the unforseen effects of drugs and genes across the whole body in both off- and on-target locations. Historeceptomics' unprecidented approach provides users with comprehensive in silico identification of drugs' receptors while also revealing their in vivo prominence in human tissues. This is the future of personalized medicine.
Utilizing a proprietary algorithm, HistoReceptomics integrates data from appropriate gene expression and protein-drug interaction databases, including BioGPS, GTeX, ChEMBL, BindingDB and our own, ever-growing database of docking results that currently includes almost 2,000 drugs docked against 6,500+ proteins with more than 352,000 hits. Search results generate a unique number calculated for each specific target-tissue pair, the HistoReceptomics (HR) Score, a ranking combining the affinity of a drug for a given protein target with the expression level of that target in the tissue.
Understanding drugs' formerly unknown or only partially known mechanisms of action is valuable on a variety of fronts, with many far-reaching applications within the spheres of drug development, drug repurposing and personalized medicine, including:
The identfication of molecular signatures for drugs with polypharmacologic modes of action
The detection of tissue-specific adverse effects of drugs
Matching molecular signatures of a disease to drugs
Target identification for bioactive compounds with unknown receptors
Hypothesis generation for drug/compound phenotypes
Enabling patient/subject stratification to maximize the probability of FDA approval
At the Historeceptomics.com website, after signing up for a free trial, users can also perform orthogonal HR searches using Target Search, a reverse search from the Compound Search, which returns the full panel of tissues in which a target is expressed; Tissue Search, which returns the full panel of targets and drugs specific to a chosen tissue (e.g. skin); and Reverse Target Search, which reveals a list of drugs or drug-like compounds that bind to a target of interest.
Molsoft, LLC's ICM-Pro, ICM-Bio, and ICM-Chemist-Pro have incorporated GeneCentrix' HR Compound Search, such that one can obtain a full HR Score profile (table of target-tissue pairs for the human body) of any drug at the click of a button, and then operate Molsoft's extensive algorithms (plotting, machine learning, cheminformatics, etc) on that data.
Find scientific journal articles related to the Historeceptomic philosophy here.
Read a case study validating the Historeceptomic approach.
For how Historeceptomics connects to topical issues in drug development, peruse our blog.