RETRACTED ARTICLE: Orphan receptor ligand discovery by pickpocketing pharmacological neighbors
Authors: R Peter Riek
Irina Kufareva
Nicola J Smith
Robert M Graham
James L J Coleman
Alastair G Stewart
Fiona M McRobb
Ruben Abagyan
Andrey V Ilatovskiy
Tony Ngo
Journal: Nature Chemical Biology (2017)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: pharmacological similarity; G protein-coupled receptors (GPCRs); ligand off-target effects; drug repurposing; ligand discovery
Affiliations: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia., St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia., Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA., Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.

Abstract:  Understanding the pharmacological similarity of G protein-coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor-ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR-CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding-site similarity that is informed by patterns of ligand-residue interactions observed in crystallographically characterized GPCRs. GPCR-CoINPocket is applicable to receptors with unknown structure or ligands and accurately captures known pharmacological relationships between GPCRs, even those undetected by phylogeny. When applied to orphan receptor GPR37L1, GPCR-CoINPocket identified its pharmacological neighbors, and transfer of their pharmacology aided in discovery of the first surrogate ligands for this orphan with a 30% success rate. Although primarily designed for GPCRs, the method is easily transferable to other protein families. 

Retracted: Yes

PubPeer comments:
 Interesting set of data. I have a couple of questions to the authors. 1. The corresponding being Subject M0: It is not uncommon for scientists fine-tuning their methodology on some of themselves in the pilot stage, but it is unusual reporting data obtained on their own body in the final publication. My question: was subject M0 (the corresponding himself) included in the reported sample of 42 subjects? I was hoping the supplemental materials might provide some clue but wasnu2019t able to access the supplemental data following the link provided in the paper. 2. Number of days (or number of rooms) taken to complete the experimental protocol: It was described that 42 subjects took tea and were IR filmed, one type of teas a day. Each subject was in the room for 20 min, for thermal equilibrium I assume, then drank tea three times in 30 min, and IR images were taken ventral and dorsal after each time of drinking tea. It is fair to assume 55 min for one subject to complete the protocol. And the authors had 25 female subjects, meaning 25 hours were necessary for one tea for the group of females. When it was also described u201cOnly one kind of tea was prepared in one day for all volunteersu201d, how was the data collection protocol accomplished? Did more than one room for each group, meaning multiple IR cameras, were used, or more than 1 day was needed to complete the protocol for each individual tea? 3. Interaction between the effects of a) timing of opening the meridian, and b) that of drinking a tea prep The authors asserted that one reason previous studies were not able to clearly show the meridian IR map was the lack of meridian opening beyond their natural opening time (and the magnitude of opening as well?), and therefore, their use of 12 teas to sort of activate the meridian opening was proposed with such a justification. By selecting 12 teas, the authors suggested a meridian-specific tea effect, other than the natural timing effect. Per the description of the above question 2, on the day of the i-th tea (i = 1:12) which supposedly to activate the i-th meridian, at least more than 2 hours were needed to collect the full data set from all subjects. Obviously, only subjects whose experiment fell in the 2 hours specific opening time for the i-th meridian would have tea-effect + timing effect, while others would have tea-effect - timing effect, and this interaction should change day by day, because a different tea was used on a different day. Was this interaction included in your statistical analysis model? 4. Order effects For each tea, there were 42 subjects, while for each subject, there were 12 teas each on a different day. Based on u201cOnly one kind of tea was prepared in one day for all volunteersu201d, likely all subjects moved together from one tea to another day after day. In this setup, there were, potentially, 2 order effects involved. One was, on a given day, the order of subjects entering the tea-drinking-IR imaging protocol. The other would be the order of teas along the days of intervention. Were these 2 order effects taken into account in your analysis model? 5. Pre-tea IR images? I didn t see any pre-tea IR images taken for each subject each day tea. If I missed the description somehow, apologize in advance. ,