The Structure Based Combination Drug Design and RAGE for Diabetic Retinopathy

Abstract

BackgroundDiabetic Retinopathy (DR) is the leading cause of blindness, stimulating the rise in 20,000 cases in the United States per year in patients with Type II Diabetes. Hyperglycemia is a major risk factor of Type II diabetes leads to the formation of plasma proteins known as Advanced Glycation End Products (AGEs) which bind to the receptor of the Advanced Glycation End Products (RAGEs) lead to DR.PurposeThe purpose of the study is to analyze drug targets (single drugs and combination of drugs) that are currently marketed for heart disease, diabetes, and hypertension and how they interact with RAGE to inhibit the ligand‐receptor interaction.MethodsThis study used molecular docking processes to analyze single and combination drug interactions with RAGE. By using AutoDock Tools and AutoDock Vina, docking simulations can identify the drug targets that can potentially decrease the severity of Diabetic Retinopathy. Molecular drug targets selected for this study were chosen from therapeutics that currently exists in the market. Selection of drugs focused on those which were commonly used for treating inflammatory conditions, such as cardiovascular disease, hyperglycemia, and cholesterol lowering drugs. The Receptor Antagonist Peptide (RAP) is a novel ligand inhibitor that has been shown to inhibit binding interaction between RAGE and many of its ligands for instance AGEs. RAP will represent the control ligand that will be able to bind to the RAGE receptor, and its binding affinity and visual orientation will be observed using a molecular docking software. The study included six (6) single drugs such as Atorvastatin, Enalapril, Fenofibrate, Lisinopril, Lovastatin and Metformin were selected to interact with the RAGE receptor. The Centers for Medicaid and Medicare Services (CMS) Prescription Drug Data Part D was used to determine which drug combinations currently exist within the market. Eight (8) drug combinations such as Canagliflozin + Metformin; Ezetimibe + Atorvastatin; Ezetimibe+ Simvastatin; Hydrochlorothiazide+ Losartan; Lisinopril +Hydrochlorothiazide; Lovastatin+ Niacin; Metformin+ Repaglinide; Telmisartan +Amlodipine were selected to test interaction with the RAGE receptor.. The affinity results were analyzed using the Lamarck's Algorithm. Based on these results the drug target and receptor files were input into AutoDock Tools to create a 3D model of the binding between the drug and receptor. AutoDock Tools was used to label the residue sequences of the binding area to create a visual orientation of the drug and receptor.ResultsBased on a single drug interaction with RAGE, cholesterol lowering drugs such as Atorvastatin and Fenofibrate were able to bind to RAGE with a high hydrophobicity and great negative affinity. In combination of Hypertensive drugs such as Telmisartan and Amlodipine could bind to the RAGE receptor, and had a high hydrophobicity and high negative affinity. These results suggest combination drugs may inhibit RAGE and may reduce the risk of diabetic retinopathy.ConclusionOverall, combination of hypertensive drugs and cholesterol lowering drugs alone may decrease the progression of DR in type II diabetes.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.