راضیه رضوی پاریزی

Sertraline, awidelyprescribedselectiveserotoninreuptakeinhibitor(SSRI),isprimarilymetabolizedbycytochromeP450en- zymes, particularlyCYP2B6,CYP2C19,andCYP3A4.However,themolecularbasisofitsinteractionwithCYP2B6andthe determinants ofitsbindingstabilityremainincompletelyunderstood.Inthisstudy,sertralineoptimizationwasperformedusing density functionaltheory(DFT)attheB3LYP/6–311 þ G(d,p) level.Thereactivityofsertralinewasexaminedviaitsfrontier molecular orbitals.TheHOMOandLUMOenergieswerefoundtobe �5.53 eVand �1.03 eV,respectively,and10regionsof chemical activitywereidentiAed.Inthisstudy,moleculardockingsimulationswereperformedusingtheMolecularOperating Environment (MOE)toinvestigatethebindingmode,energetics,andkeyinteractionsbetweensertralineandCYP2B6.The docking resultsindicatethatsertralineoccupiestheactivesiteofCYP2B6withafavorablebindingorientation,characterizedby a calculatedbindingfreeenergy(
G) of �8.22 kcal/mol.Thecomplexisprimarilystabilizedbyanetworkofnoncovalentin- teractions. Hydrogenbondsareformedbetweensertralineandseveralimportantactive-siteresidues,includingglutamate,glycine, histidine, aspartate,tyrosine,andarginine.Inaddition,hydrophobiccontactsand – stacking betweenthechlorophenylgroupof sertraline andaromaticbindingpocketresiduesalsostabilizethecomplex.Together,theseAndingselucidatethemolecularbasisof sertraline bindingtoCYP2B6andexplainitsmetabolicselectivity,aidingtheinterpretationofinterindividualvariabilityinits metabolism.