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

Abstract

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.

Fig 1. Structural comparison of the selected class B GPCRs.

Yellow—GCGR (5XEZ), pink—GIPR (4L6R), green—GLP1R (5VEW). Two binding sites (orthosteric and allosteric) were depicted as yellow spheres. The binding site for allosteric modulators of the selected class B GPCRs was shown in details on the right. The figure was prepared with Pymol [131].

Fig 2. VS results for the selected drug classes.

Here, we presented average values of XP-GScores obtained from virtual screening against all gut hormone receptors structures. We indicated error bars equal to standard deviations.

Fig 3. VS results for drugs selected from SIDER.

Here, we presented values of XP-GScores for drugs selected from the SIDER database. Drugs were ranked with respect to the percentage of DM cases reported during the treatment. VS results for each gut hormone receptor were presented separately. For the sake of clarity, only one binding site for each receptor was presented here. We selected the binding site for which the Pearson correlation coefficient between the drug ranking based on XP-GScores and the drug ranking based on SIDER was the highest.

Fig 4. VS results for statins.

Comparison of binding affinities (best XP-GScore) for the selected GPCRs with the drug ranking based on clinical trials involving diabetic patients. Assigned ranks according to [98]: 1 –pitavastatin, 2 –pravastatin, 3 –rosuvastatin, 4—atorvastatin, 5 –simvastatin, 6 –fluvastatin.

Fig 5. Rosuvastatin vs. simvastatin—The allosteric binding mode to GCGR predicted by Glide.

(A) Binding mode of rosuvastatin—the allosteric site of GCGR. The salt bridge was formed between the carboxyl group of the statin and the amino group of the well-conserved R6.35 (B) Binding mode of simvastatin—the allosteric site of GCGR. Several polar contacts were formed with the receptor, e.g., with S6.41. Polar contacts were depicted with yellow dashed lines. The figure was prepared with Pymol [131].

Fig 6. Rosuvastatin vs. simvastatin—The allosteric binding to GCGR predicted by Autodock VINA.

Rosuvastatin (A) and simvastatin (B) binding modes were obtained with Autodock VINA implemented in GUT-DOCK. Here, we submitted to GUT-DOCK the mol2 files with ligands coordinates. Polar contacts with side chains were depicted with dashed yellow lines. Polar contacts with the main chain atoms were excluded for the sake of the figure clarity. Like presented in Fig 5, rosuvastatin formed polar contacts with R6.35, while simvastatin only with S6.41. The figure was prepared with Pymol [131] and Ligplot [132] implemented in GUT-DOCK.