Prediction and validation of enzyme and transporter off-targets for metformin

Yee, Sook Wah; Lin, Lawrence; Merski, M.; Keiser, Michael J.; Gupta, Aakash; Zhang, Youcai; Chien, Huan‐Chieh; Shoichet, Brian K.; Giacomini, Kathleen M.

doi:10.1007/s10928-015-9436-y

Cited by 42 publications

(40 citation statements)

References 78 publications

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“…Duodenal biopsy study on metformin-naive individuals found that metformin stimulated the release of serotonin (5-HT) from enterochromaffin cells [28]; however, this effect is not through the 5-HT3 receptor, as the response is not altered if receptor is inhibited. Alternatively it could be explained that, the uptake of metformin via SERT or Organic Cation Transporter (OCT1) results in decreased transport of serotonin and results in GI side-effects [29].…”

Section: Mechanism Of Metformin Induced Gastrointestinal Side Effectsmentioning

confidence: 99%

Metformin and its gastrointestinal problems: A review

Fatima¹,

Sadeeqa²,

Nazir³

2018

biomedicalresearch

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Metformin is a biguanide class of drugs and has been recommended as first-line therapy for type 2 diabetes. It has a good safety profile, efficacy, comparatively reduced cost, and potential cardiovascular benefits. Metformin is an insulin-sensitizing agent, its bioavailability is 50%-60%. Generally, A1C levels are lowered by 1.5% points by metformin monotherapy. Treatment with metformin decreases fasting plasma glucose concentrations by 25% to 30% and decreases the production of glucose. Metformin reduces hepatic glucose production and absorption of glucose in the intestine. In addition to it, decreases fatty acids oxidation. In liver and skeletal muscles the mitochondrial function and AMP Activated Protein Kinase (AMPK) activity are considered as potential mechanisms and has gained much attention by which metformin exerts its advantageous effects. In the gut enteroendocrine cells secret glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are considered as important determinants for the disposal of glucose following a meal. Glucose production is reduced either by decreasing gluconeogenesis or by glycogenolysis. Treatment with metformin is, nevertheless, very often associated with gastrointestinal side effects and quality of life and treatment adherence is negatively affected in patients of type 2 diabetes. The most common gastrointestinal symptoms are diarrhea, heartburn, and nausea, followed by abdominal pain, bloating, and retching. The mechanism lying under gastrointestinal intolerance caused by metformin is unclear. However, there are different hypothesis proposed, including stimulation of intestinal secretion of serotonin, alteration in incretin and metabolism of glucose, and malabsorption of bile salts. Metformin is used clinically in diabetes, polycystic ovary syndrome, and in obese for weight reduction. It has cardioprotective effect and its use is recently being studied in cancer and HIV associated metabolic abnormalities.

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Section: Mechanism Of Metformin Induced Gastrointestinal Side Effectsmentioning

confidence: 99%

Metformin and its gastrointestinal problems: A review

Fatima¹,

Sadeeqa²,

Nazir³

2018

biomedicalresearch

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“…Despite its clinical importance, the underlying pathophysiology of metformin intolerance is not yet clear. However multiple possible hypotheses have been proposed including high intestinal metformin concentration (3,4), its effect on the gut microbiota (5), altered transportation of serotonin or direct serotonergic effects (6), and reduced ileal absorption of bile acid salts (7).…”

Section: Introductionmentioning

confidence: 99%

Variation in the plasma membrane monoamine transporter (PMAT, encoded in SLC29A4) and organic cation transporter 1 (OCT1, encoded in SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes: an IMI DIRECT study

Dawed

Zhou

Leeuwen

et al. 2018

Preprint

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Objectives: 20-30% of patients with metformin treated type 2 diabetes experience gastrointestinal side effects leading to premature discontinuation in 5-10% of the cases.Gastrointestinal intolerance may reflect localised high concentrations of metformin in the gut.We hypothesized that reduced transport of metformin into the circulation via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe GI side effects.Research Design and Methods: The study included 286 severe metformin intolerant and 1128 tolerant individuals from the IMI DIRECT consortium. We assessed the association of patient characteristics, concomitant medication and the burden of mutations in the SLC29A4 and SLC22A1, genes that encode PMAT and OCT1, respectively, on odds of metformin intolerance using a logistic regression model.Results: Women (p < 0.001) and older people (p < 0.001) were more likely to develop metformin intolerance. Concomitant use of metformin transporter inhibiting drugs increased the odds of intolerance by more than 70% (OR = 1.72 [1.26-2.32], p < 0.001). In a logistic regression model adjusted for age, sex, weight and population substructure, the G allele at rs3889348 (SLC29A4) was associated with GI intolerance (OR = 1.34[1.09-1.65], p = 0.005).rs3889348 is the top cis-eQTL for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with metformin transporter inhibiting drugs had over three times higher odds of intolerance compared to carriers of no G allele and not treated with inhibiting drugs (OR = 3.23 [1.71-6.39], p < 0.001). Using a genetic risk score (GRS) derived from SLC29A4 (rs3889348) and previously reported SLC22A1 variants (M420del, R61C, G401S), the odds of intolerance was more than twice in individuals who carry three or more risk alleles compared with those carrying none (OR = 2.15 [1.20-4.12], p = 0.01). 4Conclusions: These results suggest that intestinal metformin transporters and concomitant medications play an important role in gastrointestinal side effects of metformin.

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“…We explored which combinations of conformer generation and E3FP parameters produced the most effective 3D fingerprints for the task of recovering correct ligand binders for over 2,000 protein targets using the Similarity Ensemble Approach (SEA). SEA compares sets of fingerprints against each other using Tanimoto coefficients (TC) and determines a p-value for the similarity among the two sets; it has been used to predict drug off-targets 4,5,37,38 , small molecule mechanisms of action [39][40][41] , and adverse drug reactions 4,42,43 . For the training library, we assembled a dataset of small molecule ligands that bind to at least one of the targets from the ChEMBL database with an IC 50 of 10 μM or better.…”

Section: Sea 3d Fingerprint Performance Exceeds That Of 2d In Bindingmentioning

confidence: 99%

A simple representation of three-dimensional molecular structure

Axen

Huang

Cáceres

et al. 2017

Preprint

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Statistical and machine learning approaches predict drug-to-target relationships from 2D smallmolecule topology patterns. One might expect 3D information to improve these calculations.Here we apply the logic of the Extended Connectivity FingerPrint (ECFP) to develop a rapid, alignment-invariant 3D representation of molecular conformers, the Extended ThreeDimensional FingerPrint (E3FP). By integrating E3FP with the Similarity Ensemble Approach (SEA), we achieve higher precision-recall performance relative to SEA with ECFP on ChEMBL20, and equivalent receiver operating characteristic performance. We identify classes of molecules for which E3FP is a better predictor of similarity in bioactivity than is ECFP.Finally, we report novel drug-to-target binding predictions inaccessible by 2D fingerprints and confirm three of them experimentally with ligand efficiencies from 0.442 -0.637 kcal/mol/heavy atom.

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Prediction and validation of enzyme and transporter off-targets for metformin

Cited by 42 publications

References 78 publications

Metformin and its gastrointestinal problems: A review

Metformin and its gastrointestinal problems: A review

Variation in the plasma membrane monoamine transporter (PMAT, encoded in SLC29A4) and organic cation transporter 1 (OCT1, encoded in SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes: an IMI DIRECT study

A simple representation of three-dimensional molecular structure

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