ABSTRACT
This review presents the main aspects related to pharmacokinetic properties, which are essential for the efficacy and safety of drugs. This topic is very important because the analysis of pharmacokinetic aspects in the initial design stages of drug candidates can increase the chances of success for the entire process. In this scenario, experimental and inâ silico techniques have been widely used. Due to the difficulties encountered with the use of some experimental tests to determine pharmacokinetic properties, several inâ silico tools have been developed and have shown promising results. Therefore, in this review, we address the main free tools/servers that have been used in this area, as well as some cases of application. Finally, we present some studies that employ a multidisciplinary approach with synergy between inâ silico, inâ vitro, and inâ vivo techniques to assess ADME properties of bioactive substances, achieving successful results in drug discovery and design.
Subject(s)
Drug Design , Pharmaceutical Preparations/chemistry , Animals , Humans , Molecular Structure , Pharmaceutical Preparations/chemical synthesisABSTRACT
INTRODUCTION: The enzyme called dipeptidyl peptidase IV (DPP-IV) is related to the glycemic control associated with the stimulation of the pancreas to produce insulin. So, its inhibition is a good strategy for the treatment of type 2 diabetes mellitus. METHODS: In this study, we have employed molecular modeling strategies such as CoMFA, molecular docking, molecular dynamics, and binding free energy calculations of a set of DPP-IV inhibitors in order to understand the main characteristics related to the biological activity of these ligands against the enzyme. RESULTS: The models obtained from CoMFA presented significant values of internal (0.768) and external (0.988) validations. Important interactions with some residues, such as Glu205, Tyr666, Arg125, Ser630, Phe357 and Tyr662, were also identified. In addition, calculations of the electronic properties allowed relating the LUMO and HOMO energies with the biological activity of the compounds studied. The results obtained from the molecular dynamics simulations and the SIE calculations (ΔG) indicated that the inhibitor 40 increases the stability of the DPP-IV target. CONCLUSIONS: Therefore, from this study, it is possible to propose molecular modifications of these DPP-IV inhibitors in order to improve their potential to treat type 2 diabetes.
Subject(s)
Computer Simulation , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/pharmacology , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Conformation , ThermodynamicsABSTRACT
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.
