In Silico Searching for Alternative Lead Compounds to Treat Type 2 Diabetes through a QSAR and Molecular Dynamics Study.

Nicolás Cabrera,José R Mora,Edgar A Márquez,Sebastián A Cuesta,José Luis Paz,Luis Calle,Roland Kaunas

doi:10.3390/pharmaceutics14020232

Abstract

Free fatty acid receptor 1 (FFA1) stimulates insulin secretion in pancreatic β-cells. An advantage of therapies that target FFA1 is their reduced risk of hypoglycemia relative to common type 2 diabetes treatments. In this work, quantitative structure–activity relationship (QSAR) approach was used to construct models to identify possible FFA1 agonists by applying four different machine-learning algorithms. The best model (M2) meets the Tropsha’s test requirements and has the statistics parameters R2 = 0.843, Q2CV = 0.785, and Q2ext = 0.855. Also, coverage of 100% of the test set based on the applicability domain analysis was obtained. Furthermore, a deep analysis based on the ADME predictions, molecular docking, and molecular dynamics simulations was performed. The lipophilicity and the residue interactions were used as relevant criteria for selecting a candidate from the screening of the DiaNat and DrugBank databases. Finally, the FDA-approved drugs bilastine, bromfenac, and fenofibric acid are suggested as potential and lead FFA1 agonists.

Highlights

Diabetes mellitus affected approximately 463 million people worldwide (~9.3% of the population) in 2019, with numbers expecting to rise to 578 million (~10%) by 2030 and 700 million (~11%) by 2045 [1]
Type 2 Diabetes Mellitus (T2DM) is characterized by reduced secretion of insulin from β-cells and resulting hyperglycemia associated with cardiovascular complications such as cardiac ischemia and stroke [3,4]
Free Fatty Acid Receptor 1 (FFA1), a protein expressed in pancreatic β-cell, has become a target of interest since FFA1 activation through ligand-receptor binding induces insulin

Summary

Introduction

Diabetes mellitus affected approximately 463 million people worldwide (~9.3% of the population) in 2019, with numbers expecting to rise to 578 million (~10%) by 2030 and 700 million (~11%) by 2045 [1]. Type 2 Diabetes Mellitus (T2DM) is the most common type of diabetes, representing 80% of all the cases [2]. T2DM is characterized by reduced secretion of insulin from β-cells and resulting hyperglycemia associated with cardiovascular complications such as cardiac ischemia and stroke [3,4]. Current methods to control blood sugar, including controlled diet, metformin, sulfonylurea, and insulin [5], have limited efficacy and are associated with potential health problems such as hypoglycemia, weight gain, and lack of sustained efficacy [6,7,8]. Pharmaceutics 2022, 14, 232 secretion [7]. Metformin, and sulfonylurea, induction of insulin in response to FFA1 agonists is attenuated when blood glucose levels are excessive, providing negative feedback that reduces the risk of hypoglycemia [9]

Methods

Results

Conclusion