Theoretical Study On The Interaction Of FABP5/7 With Its Inhibitors And The Pharmacokinetics Of Pt(Ⅳ) Prodrugs

Fatty acid-binding proteins（FABPs）,particularly FABP5 and FABP7,are intracellular transporters of anandamide（AEA）,an endocannabinoid.Studies in animals have indicated that the elevation of anandamide levels produces beneficial pharmacological effects on stress,pain,and inflammation,as well as improves the effects of withdrawal.In this work,we carried out a comprehensive investigation into the recognition characteristics and the mechanism of inhibition by SBFI-26 of FABP5/7 for anandamide through molecular dynamics simulations.We found that（1）in the FABP5＿AEA system,the key residues involved in recognizing AEA were primarily R129,Y131,A78,P41,and F19,and electrostatic interactions dominated over van der Waals interactions;whereas in the FABP7＿AEA system,the key residues were slightly different and included R127,R107,Y129,T54,and P39,and van der Waals interactions were relatively stronger.Thus,the differences in recognition characteristics of AEA by FABP5 and FABP7 were first reflected in the different residues and secondly in the different driving forces for recognition.（2）Interestingly,in the FABP5＿8KS and FABP7＿8KS systems,8KS almost replicated the recognition pattern of AEA by engaging similar residues in similar ways.Of course,there were differences,such as the higher binding affinity of 8KS with the protein than AEA,the stronger electrostatic effects of8KS with the key residues,and the dominance of electrostatic interactions in both systems.Although electrostatic energy and van der Waals force are both important driving forces for AEA-level 8KS recognition of FABP5/7,in the FABP5 system,both entropy and enthalpy were contributing,while in the FABP7 system,the driving force was mainly enthalpy.Platinum-based chemotherapy,including cisplatin,carboplatin,and oxaliplatin,has achieved tremendous success in clinical settings,but their nonspecific activation and drug resistance have hindered their widespread use due to toxic side effects.Selective activation of prodrugs within tumors has been widely explored for tumor chemotherapy because it causes minimal damage to normal tissues.The development of platinum-based photosensitizing prodrugs has significant application prospects.The photophysical properties of Pt prodrugs,including cisplatin,carboplatin,and oxaliplatin,with six coordination and complexes with different ligand substitution,are essential for rational ligand design since the photodynamic strategy can control the time and location of drug action.The influence of different substituents on the longitudinal axis of the absorption spectra of the coordination compounds was studied within the theoretical framework of time-dependent density functional theory.On the other hand,the strength of the ligand-metal coordination bond plays a crucial role in determining the dissociation ability of six-coordinated Pt prodrugs and their effectiveness in vivo.Therefore,it is essential to adopt a suitable method to evaluate the strength of the coordination bond.Considering the successful application of the IGM-IBSI method in determining the strength of Pt drug coordination bonds,this method was used to investigate six-coordinated Pt prodrugs.Finally,the stability and electrophilicity of the obtained complexes were evaluated based on the hardness and electrophilicity index defined by conceptual density functional theory.The following three conclusions were drawn:（1）Appropriate extension of the carbon chain and nitrogen substitution near the carbonyl group can regulate the absorption peak and absorption region of the compounds within a certain range;Nitrogen substitution on the carbonyl group adjacent to the metal center can cause a blue shift of the spectra or absorption peaks and significantly affect the absorption intensity.The different electronegativities do not have a regular effect on the spectral range and absorption peaks of the system.（2）Introduction of electron-withdrawing groups by X₂ligands can greatly enhance the dissociation ability of the three types of Pt（Ⅳ）complexes,but the effect of carbon chain extension varies in different systems.However,the effect of nitrogen substitution on the carbonyl group adjacent to the ligand on the dissociation ability of the complex also varies.（3）The length of the carbon chain of the substituent on the axial ligand has no significant effect on the stability of all complexes,while the effect of electronegativity varies in systems with different substituents on X₁;as the electronegativity increases,the stability of the system decreases in the system where X₁ is a methoxyamide substituent,but the opposite effect is observed in the system where X₁ is a methyl substituent.In addition,as the carbon chain length increases,the electrophilicity of the system does not change significantly,but as the electronegativity of the ligand increases,the electrophilicity of the system increases,and nitrogen substitution on the carbonyl group adjacent to the metal center can enhance the electrophilicity of the system in some systems.