A benchmarking study on virtual ligand screening against homology models of human GPCRs

Lim, Victor Jun Yu; Du, Weina; Chen, Yu Zong; Fan, Hao

doi:10.1002/prot.25533

Cited by 13 publications

(9 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It thus appears that the biasing is dependent on 1 or more of these deep‐pocket interactions. Despite the exploratory nature of these modeling results and the limitations of docking to GPCR crystal structures and homology models (45), they point to potential unique interactions of DPD and ORP with the receptor. These compounds may lock the receptor‐β‐arrestin complex in some way to mitigate internalization.…”

Section: Discussionmentioning

confidence: 99%

Differential long‐term regulation of TAS2R14 by structurally distinct agonists

et al. 2019

View full text Add to dashboard Cite

Bitter taste receptor‐14 (TAS2R14) is a GPCR also expressed on human airway smooth muscle cells, which signals to intracellular [Ca2+], resulting in relaxation of the airway, and is a novel target for bronchodilators. Here, we examine long‐term, agonist‐promoted down‐regulation of TAS2R14 expression because tachyphylaxis would be an undesirable therapeutic characteristic. Five TAS2R structurally distinct full agonists were studied to ascertain biasing away from down‐regulation. Agonist exposure for 18 h caused minimal desensitization by diphenhydramine (DPD) compared with ~50% desensitization with all other agonists. Agonists evoked β‐arrestin recruitment to TAS2R14, which was not seen with a phosphoacceptor‐deficient mutant, TAS2R14‐10A. All agonists except for DPD also caused subsequent TAS2R14 internalization and trafficking via early and late endosomes to down‐regulation. TAS2R14‐10A failed to undergo these events with any agonist. Molecular docking showed that DPD has specific interactions deep within a binding pocket that are not observed with the other agonists, which may lock the receptor in a conformation that does not internalize and therefore does not undergo down‐regulation. Thus, TAS2R14 is subject to β‐arrestin‐mediated internalization and subsequent down‐regulation with chronic exposure to most agonists. However, by manipulating the agonist structure, biasing toward G‐protein coupling but away from long‐term down‐regulation can be achieved.—Woo, J. A., Castaño, M., Goss, A., Kim, D., Lewandowski, E. M., Chen, Y., Liggett, S. B. Differential long‐term regulation of TAS2R14 by structurally distinct agonists. FASEB J. 33, 12213‐12225 (2019). http://www.fasebj.org

show abstract

Section: Discussionmentioning

confidence: 99%

Differential long‐term regulation of TAS2R14 by structurally distinct agonists

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In the next step of our modeling pipeline GPCR models were evaluated in the first stage VS procedure (enrichment studies) to retrieve the best-performing in VS receptors structures, following a well-established approach described, e.g., in [118]. For that first stage VS we used a set of 10 known active ligands retrieved from BindingDB [119] and Pubchem databases [120] for each receptor (see [25]) and 500 decoys (50 for each active ligand) generated via the DUD-E website (http://dude.docking.org/) [121].…”

Section: Methodsmentioning

confidence: 99%

Drug-induced diabetes type 2: In silico study involving class B GPCRs

et al. 2019

View full text Add to dashboard Cite

A disturbance of glucose homeostasis leading to type 2 diabetes mellitus (T2DM) is one of the severe side effects that may occur during a prolonged use of many drugs currently available on the market. In this manuscript we describe the most common cases of drug-induced T2DM, discuss available pharmacotherapies and propose new ones. Among various pharmacotherapies of T2DM, incretin therapies have recently focused attention due to the newly determined crystal structure of incretin hormone receptor GLP1R. Incretin hormone receptors: GLP1R and GIPR together with the glucagon receptor GCGR regulate food intake and insulin and glucose secretion. Our study showed that incretin hormone receptors, named also gut hormone receptors as they are expressed in the gastrointestinal tract, could potentially act as unintended targets (off-targets) for orally administrated drugs. Such off-target interactions, depending on their effect on the receptor (stimulation or inhibition), could be beneficial, like in the case of incretin mimetics, or unwanted if they cause, e.g., decreased insulin secretion. In this in silico study we examined which well-known pharmaceuticals could potentially interact with gut hormone receptors in the off-target way. We observed that drugs with the strongest binding affinity for gut hormone receptors were also reported in the medical information resources as the least disturbing the glucose homeostasis among all drugs in their class. We suggested that those strongly binding molecules could potentially stimulate GIPR and GLP1R and/or inhibit GCGR which could lead to increased insulin secretion and decreased hepatic glucose production. Such positive effect on the glucose homeostasis could compensate for other, adverse effects of pharmacotherapy which lead to drug-induced T2DM. In addition, we also described several top hits as potential substitutes of peptidic incretin mimetics which were discovered in the drug repositioning screen using gut hormone receptors structures against the ZINC15 compounds subset.

show abstract

“…The accuracy of the virtual screening was assessed using enrichment factor (EF) and logarithmic area under curve (logAUC), as described in Eqs. 2 and 3 (Fan et al 2009(Fan et al , 2012Mysinger and Shoichet 2010;Mysinger et al 2012;Lim et al 2018). The EF is the concentration of the true positives among the top-scoring docking hits compared to their concentration throughout the entire database:…”

Section: Evaluation Of Virtual Screening Resultsmentioning

confidence: 99%

“…Active total Δx and x = log 10 N subset N total , across all receptor structures (Fan et al 2009;Lim et al 2018).…”

Section: Evaluation Of Virtual Screening Resultsmentioning

confidence: 99%

Virtual screening of potentially endocrine-disrupting chemicals against nuclear receptors and its application to identify PPARγ-bound fatty acids

Jaladanki

Zhao

et al. 2020

Arch Toxicol

Self Cite

View full text Add to dashboard Cite

Nuclear receptors (NRs) are key regulators of energy homeostasis, body development, and sexual reproduction. Xenobiotics binding to NRs may disrupt natural hormonal systems and induce undesired adverse effects in the body. However, many chemicals of concerns have limited or no experimental data on their potential or lack-of-potential endocrine-disrupting effects. Here, we propose a virtual screening method based on molecular docking for predicting potential endocrine-disrupting chemicals (EDCs) that bind to NRs. For 12 NRs, we systematically analyzed how multiple crystal structures can be used to distinguish actives and inactives found in previous high-throughput experiments. Our method is based on (i) consensus docking scores from multiple structures at a single functional state (agonist-bound or antagonist-bound), (ii) multiple functional states (agonist-bound and antagonist-bound), and (iii) multiple pockets (orthosteric site and alternative sites) of these NRs. We found that the consensus enrichment from multiple structures is better than or comparable to the best enrichment from a single structure. The discriminating power of this consensus strategy was further enhanced by a chemical similarity-weighted scoring scheme, yielding better or comparable enrichment for all studied NRs. Applying this optimized method, we screened 252 fatty acids against peroxisome proliferator-activated receptor gamma (PPARγ) and successfully identified 3 previously unknown fatty acids with Kd = 100–250 μM including two furan fatty acids: furannonanoic acid (FNA) and furanundecanoic acid (FUA), and one cyclopropane fatty acid: phytomonic acid (PTA). These results suggested that the proposed method can be used to rapidly screen and prioritize potential EDCs for further experimental evaluations.

show abstract

A benchmarking study on virtual ligand screening against homology models of human GPCRs

Cited by 13 publications

References 43 publications

Differential long‐term regulation of TAS2R14 by structurally distinct agonists

Differential long‐term regulation of TAS2R14 by structurally distinct agonists

Drug-induced diabetes type 2: In silico study involving class B GPCRs

Virtual screening of potentially endocrine-disrupting chemicals against nuclear receptors and its application to identify PPARγ-bound fatty acids

Contact Info

Product

Resources

About