Molecular simulations of platinum-based anticancer drugs interacting with potential drug delivery systems

In therapidlyevolvingfieldofdrugdelivery,computationalmethodssuchas molecular dynamics(MD)simulationshavebecomeindispensabletoolsforun- derstanding complexinteractionsatthemolecularlevel.ThisthesisusesMD to investigatetheadsorptionbehaviorandinteractionsofplatinum-basedan- titumor agentswithnanoscaledrugdeliverysystems,focusingontwodistinct nanovehicles:grapheneandhumanserumalbumin(HSA).Thesesystemsrep- resentcomplementaryapproachesinnanomedicine,withgrapheneknownfor its extraordinaryadsorptioncapacityduetoitshighsurfaceareaandporous structure, andHSAforitsspecificity,biocompatibility,andbiodegradability. The platinum-basedcompoundsstudiedincludecisplatin(CPT),monoand diaquo-derivatives(WCPTandW2CPT),andphenanthriplatin(PPT),which wereexploredfortheirinteractiondynamicswithgraphenesurfacesandHSA. MD simulationsrevealthatplatinum-basedcomplexesspontaneouslyadsorb ontothegraphenesurface.Thisadsorptionprocessisprimarilydrivenbyen- thalpic contributions,suggestingstronginteractionsbetweenthecomplexesand the graphene.Whilegraphenedemonstratessignificantpotentialforhighdrug loading, itslackofspecificityininteractionslimitsitseffectivenessintargeted drug delivery. In contrast,HSAoffersamoresophisticatedmechanismfordrugdelivery,as it caninteractspecificallywithdrugmoleculesthroughnon-covalentbinding, including π-π stackingandhydrogenbonding.Additionally,HSAfunctions as adrugreservoirthroughreversiblecovalentbinding,significantlyenhancing drug biodistributionandbioavailability.Thesimulationsinvestigatedthenon- covalentbindingofphenanthriplatin(PPT),revealingahighaffinityforsite IIIBonhumanserumalbumin(HSA).Incontrast,cisplatin(CPT)interacts exclusivelythroughcovalentbinding,primarilywithtwokeyresidues:HIS105 and MET329.Thiscovalentbindingmechanisminvolvesthelossofchloride ions byCPTuponitsinteractionwithHSA.However,thespecificanticancer mechanismoftheHSA–CPTcomplexatthecellularlevelremainspoorlyun- derstood. Additionally,weexploredthecovalentcomplexesPPT-HSA,focusingonthe same aminoacidresidues.Ourfindingshighlighttheimportanceofbothco- valentandnon-covalentinteractionsinimprovingdrugdeliveryeffectiveness. Understanding theseinteractionscanhelpusdesignbetterdrugdeliverysys- tems, ultimatelyleadingtobettertherapeuticoutcomes.