Molecular Simulation Assisted Chiral MOFs In The Research Of Resolution Of Amlodipine Enantiomers

Chiral problems are indispensable research directions at present,which are usually involved in many fields like food safety,drug development,material application and catalyst research and related to our progress.As a typical third-generation highly effective calcium channel blocker,amlodipine has been recommended by the World Health Organization as an effective first-line antihypertensive drug for its mild efficacy,long-term efficacy and safety.However,as a chiral drug,amlodipine also has two different configurations,R-amlodipine and S-amlodipine.Compared with S-amlodipine,R-amlodipine is not only less effective,but also may cause the release of nitric oxide around blood vessels,which may result in unnecessary diseases.Therefore,chiral separation of amlodipine is of great importance to ensure safe and reliable administration process.Metal organic frameworks（MOFs）as one kind of new materials,are always used in asymmetric catalysis,separation,medicine,biochemistry and other fields due to their regular channels and flexible and adjustable chemical structures.However,there are few reports on the separation of amlodipine racemate by using chiral MOFs.Therefore,this paper mainly employs molecular simulation to assist in selecting suitable MOFs precursors,and then synthesizes chiral MOFs to carry out selective adsorption experiments on amlodipine to test its chiral separation performance.Due to the large varities and numerous different structures of MOFs,it is impractical to systematiclly study the resolution performance of each MOFs for amlodipine enantiomers.In this paper,we sreened potential amlodipine drug carriers and chiral MOFs precursors from 30 kinds of MOFs by combining GCMC method with Molecular Dynamics simuation.Then seven representative MOFs（IRMOF-74-Ⅳ、IRMOF-74-Ⅶ-oeg、IRMOF-74-Ⅸ、MIL-100、MIL-101（Al）、bio-MOF-100 and DUT-5）were chosen to systematically study their adsorption mechanism、adsorption and low-release diffusion process.This is the first study to investigate the correlations between self-diffusion coefficients of drug molecule and its adsorption heat,pore volumes and LCDs of MOF-74 series which have the same topological structure.Meanwhile the correlation mechanism between the adsorption and transport performance of MOFs as porous carrier materials for drugs and its structural characteristics was also clarified.NH₂-MIL-101（Al）and DUT-5-（NH₂）₂,which can provide free amino groups were selected as chiral modification precursors MOFs on the basis of simulation.Three chiral amino acids（L-glutamic,L-histidine and L-tryptophan）were grafted into NH₂-MIL-101（Al）organic ligands by indirect synthesis to obtain corresponding chiral MOFs,and then the synthetic chiral MOFs were carried out selective adsorption experiments to explore their chiral separation ability for amlodipine.The results showed that MIL-101-NH-L-His enantiomer overmagnitude values of amlodipine was lower（4.05%）,while the enantiomer overmagnitude values of amlodipine in MIL-101-NH-L-Glu and MIL-101-NH-L-Try were 13.75%and17.75%,respectively.This indicates that the two chiral MOFs have certain chiral recognition ability for amlodipine and are potential chiral separation materials.This work can help researchers to deeply understand the mechanism of drug adsorption,diffusion and chiral resolution in MOFs as well as their host-guest interaction from the molecular level,meanwhile,it can also provide reference value for accelerating the screening of appropriate drug carriers and chiral MOFs precursors before the experiment.