Études de différents modes d'interactions entre une cible neuro dégénérative et une nouvelle classe de molécules bioactives : Approches de Docking/Dynamique moléculaire, Replacement bioisostérique et ADME.

Abstract

Monoamine oxidase B and adenosine A2A receptors are used as key targets in Parkinson's disease. The inhibitory power of a new series of phenylxanthine derivatives on two biological targets, the hMAO-B and hA2AR, has recently been demonstrated. Consequently, in our research work we carried out a study of the interactions established between 38 phenylxanthine derivatives with the biological targets hMAO-B and hA2AR. This study is based on the use of various molecular modeling techniques. A molecular docking study revealed that compounds L24 ((E)-3-(3-Chlorophenyl)-N-(4-(1,3-dimethyl-2,6- dioxo-2,3,6, 7-tetrahydro-1H-purin-8-yl) phenyl) acrylamide and L32 ((E)-3-(3-Chlorophenyl)-N-(3-(1,3 dimethyl-2,6-dioxo- 2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)acrylamide had a high affinity with the cavities of hMAO-B and hA2AR targets (S score: -10.160 and -7.344 kcal/mol respectively), and the stability of the complexes studied was confirmed through molecular dynamics simulations. A molecular electrostatic potential (MEP) analysis of compounds 24 and 32 was also carried out. In addition, the bioisosteric replacement approach was successfully applied to design two new analogues of each compound with low energy scores. Moreover, ADME-T and Drug-likeness results revealed promising pharmacokinetic properties and oral bioavailability for these compounds. Therefore, compounds L24, L32 and their analogues can be further analyzed and optimized to design new, more effective lead compounds for the treatment of Parkinson's disease.