ABSTRACT
BACKGROUND: Due to the increasing number of diabetes cases worldwide, there is an international concern to provide even more effective treatments to control this condition. METHODS: This review brings together a selection of studies that helped to broaden the comprehension of various biological targets and associated mechanisms involved in type 2 diabetes mellitus. RESULTS: Such studies demonstrated that QSAR techniques and virtual screenings have been successfully employed in drug design projects. CONCLUSIONS: Therefore, the main goal of this review is to give the state-of-art for the development of new drugs for the treatment of type 2 diabetes mellitus and to evaluate how computational tools, such as virtual screening and 3D-QSAR, can aid the development of new drugs with reduced adverse side effects.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Hypoglycemic Agents/therapeutic use , Quantitative Structure-Activity Relationship , Animals , Dose-Response Relationship, Drug , Humans , Hypoglycemic Agents/chemistry , Models, Molecular , Molecular StructureABSTRACT
AT1 receptor is an interesting biological target involved in several important diseases, such as blood hypertension and cardiovascular pathologies. In this study we investigated the main electrostatic and steric features of a series of AT1 antagonists related to hypertensive activity using structure and ligand-based strategies (docking and CoMFA). The generated 3D model had good internal and external consistency and was used to predict the potency of an external test set. The predicted values of pIC50 are in good agreement with the experimental results of biological activity, indicating that the 3D model can be used to predict the biological property of untested compounds. The electrostatic and steric CoMFA maps showed molecular recognition patterns, which were analyzed with structure-based molecular modeling studies (docking). The most and the least potent compounds docked into the AT1 binding site were subjected to molecular dynamics simulations with the aim to verify the stability and the flexibility of the ligand-receptor interactions. These results provided valuable insights on the electronic/structural requirements to design novel AT1 antagonists.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/chemistry , Angiotensin II Type 1 Receptor Blockers/pharmacology , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Receptor, Angiotensin, Type 1/chemistry , Receptor, Angiotensin, Type 1/drug effects , Static Electricity , Angiotensin II Type 1 Receptor Blockers/metabolism , Antihypertensive Agents/metabolism , Binding Sites , Blood Pressure/drug effects , Computer-Aided Design , Drug Design , Ligands , Molecular Structure , Protein Binding , Protein Conformation , Quantitative Structure-Activity Relationship , Receptor, Angiotensin, Type 1/metabolism , Renin-Angiotensin System/drug effectsABSTRACT
Antagonists of AT1 receptor are interesting substances to develop drugs that can be used for the treatment of hypertension and other diseases that affect the cardiovascular system. This study investigates the main interactions between various AT1 antagonists and the biological target by applying fragment-based drug design (Hologram QSAR - HQSAR). The proposed HQSAR model yielded significant correlation coefficients (q(2) = 0.764 and r(2) = 0.914), indicating that the method is rigorous and reliable. All models were externally validated using a test set and the results showed good agreement between the experimental and predicted data (r(2) test = 0.740). Therefore, our model can positively contribute to understand the structural features involved in the main interactions between the AT1 antagonists and the residues of the binding site.
