The Binding Mode And The Structural Features Of The Pyrimidine Derivatives As A2A Adenosine Receptor Antagonists

A2A adenosine receptors are widely distributed in the tissues of the nervous system,cardiovascular system, digestive system and respiratory system, which play theirphysiological functions by coupling with G-protein receptor. Recent evidences havehighlighted A2A adenosine receptor (AR) as a potential therapeutic target for Parkinson'sdisease. Additionally, the blockade of A2A AR can also treat asthma, atherosclerosis, sepsis,glaucoma, cancer, depression, etc. Now, the non-xanthine type heterocyclic antagonists havebeen developed, i.e. pyrimidine derivatives, which exhibited excellent preclinicalphysiochemical and pharmacokinetic profiles, and some of which have displayed strong invivo potency and high oral bio-availability. However, there still exist several problems aboutthe molecular mechanism of pyrimidine derivatives as antagonists of human A2A AR:(1)How do the derivatives interact with the human A2A AR?(2) What is the similarity/differenceof the binding sites between these antagonists and other known A2A antagonists?(3)What arethe structural features of the derivatives indispensable for improvement of the potency?Here,278monocyclic and bicyclic pyrimidine derivatives was investigated byemploying in silico methods to elucidate the probable binding mode of the antagonists withinthe A2A AR and to insight into the structural features of these derivatives, which mighthelpful in future rational design of novel drug candidates for the treatment of some brainfunctional disorder diseases. Research contents and main results are as follows:1. All compounds were docked into the A2A AR using Autodock in SYBYL package toobtain the binding mode. Subsequently, molecular dynamics simulation was implemented forthe selected docked complexes with the highest active compound to generate the final bindingmodels of pyrimidine derivatives.The binding analysis revealed that the pyrimidinederivatives were positioned toward TM2,3,5,6and7of A2A AR, anchored by the aromaticstacking with Phe168(5.29), hydrogen bonding interactions with Glu169(5.30) andAsn253(6.55), as well as non-polar interactions with the receptor. Additionally, thecomparison of the binding poses for the above antagonists with ZM241385, XAC andcaffeine in the crystal structure revealed similarities in the side chains of amino acid residuesinvolved in ligand recognition. 2. Molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) calculations wereperformed to calculate the binding free energies for the binding modes, and the results arenegative values which confirm the reasonableness of the binding modes. By further inspectionof the individual energy, the electrostatic energy, the van der Waals interaction energy and thenonpolar solvation energy are favorable for the binding, while the polar solvation affects thebinding of the ligands in an unfavorable way.3. A set of ligand-/receptor-based three-dimensional quantitative structure-activityrelationship (3D-QSAR) models for the derivatives are generated using ComparativeMolecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis(CoMSIA) approaches, in which the models of high statistical significance were selected. Theresulting3D-QSAR contour maps correlated the structural features of the antagonists with thebinding affinity. A minor/bulky group with negative charge at C2/C6of pyrimidine ringrespectively enhances the activity for all these pyrimidine derivatives. Particularly, thebicyclic derivatives contain the higher electron density of the ring, the more potent for theantagonists.