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Abstract
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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.
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