The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate...The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.展开更多
To enhance the potential application of thermally activated delayed fluorescence(TADF)molecular materials,new functions are gradually cooperated to the TADF molecules.Aggregation induced emission can effectively solve...To enhance the potential application of thermally activated delayed fluorescence(TADF)molecular materials,new functions are gradually cooperated to the TADF molecules.Aggregation induced emission can effectively solve the fluorescence quenching problem for TADF molecules in solid phase,thus aggregation-induced delayed fluorescence(AIDF)molecules were recently focused.Nevertheless,their luminescent mechanisms are not clear enough.In this work,excited state properties of an AIDF molecule DMF-BP-DMAC[reported in Chemistry-An Asian Journal 14828(2019)]are theoretically studied in tetrahydrofuran(THF)and solid phase.For consideration of surrounding environment,the polarizable continuum method(PCM)and the combined quantum mechanics and molecular mechanics(QM/MM)method were applied for solvent and solid phase,respectively.Due to the increase of the transition dipole moment and decrease of the energy difference between the first single excited state(S1)and the ground state(S0),the radiative rate is increased by about 2 orders of magnitude in solid phase.The energy dissipation of the non-radiative process from S1 to S0 is mainly contributed by low-frequency vibrational modes in solvent,and they can be effectively suppressed in aggregation,which may lead to a slow non-radiation process in solid phase.Both factors would induce enhanced luminescence efficiency of DMF-BP-DMAC in solid phase.Meanwhile,the small energy gap between S1 and triplet excited states results in high reverse intersystem crossing(RISC)rates in both solvent and solid phase.Therefore,TADF is confirmed in both phases.Aggregation significantly influences both the ISC and RISC processes and more RISC channels are involved in solid state.The enhanced delayed fluorescence should be induced by both the enhanced fluorescent efficiency and ISC efficiency.Our calculation provides a reasonable explanation for experimental measurements and helps one to better understand the luminescence mechanism of AIDF molecules.展开更多
Objective: To study the effect of halo substitution on disubstituted aryl semicarbazones on the anticonvulsant potential and model the activity based on quantum mechanics. Methods: A series of twenty-six compounds of ...Objective: To study the effect of halo substitution on disubstituted aryl semicarbazones on the anticonvulsant potential and model the activity based on quantum mechanics. Methods: A series of twenty-six compounds of N4-(4-bromo-3-methylphenyl) semicarbazones were synthesized and evaluated for the anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Some potential compounds were also tested in the subcutaneous strychnine (scSTY) and subcutaneous picrotoxin (scPIC) seizure threshold tests. The synthesized compounds were tested for behavioral impairment and CNS (central nervous system) depression in mice. Quantum mechanical modelling was carried out on these compounds to gain understanding on the structural features essential for activity. Results: Some compounds possessed broad spectrum anticonvulsant activity as indicated by their effect in pentylenetetrazole, strychnine, picrotoxin and maximal electro- shock seizures models in resemblance to other aryl semicarbazone derivatives reported earlier. The higher the difference in HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy levels was, the greater was the activity profile. Conclusion: The pharmacophoric requirements for compounds to exhibit anticonvulsant activity that includes one aryl unit in proximity to a hydrogen donor-acceptor domain and an electron donor have been justified with the molecular orbital surface analysis of the synthesized compounds.展开更多
We used ABEEMon（atom-bond electronegativity equalization method） polarizable force field（ABEEMσπ PFF） method combined with QM and molecular dynamics-free energy perturbation（MD-FEP） methods to investigatethe f...We used ABEEMon（atom-bond electronegativity equalization method） polarizable force field（ABEEMσπ PFF） method combined with QM and molecular dynamics-free energy perturbation（MD-FEP） methods to investigatethe function of water molecules in hydrolysis process of ImH[trans-Ru（Im）2Cl4]（ICR）. The activation free energiesobtained via MD-FEP calculation are in fair agreement with the experimental data. In addition, QM/MM（ABEEM）rationally describes the charge distributions and the electrostatic interaction between molecules. ABEEMσπ fluctua-ting charge model has the following good characteristics： （1） not only atomic charge regions but also σ,π bond andlone pair charge regions are explicitly represented for a molecule; （2） the region charges are geometry dependent andcalculated from time to time in the dynamic simulation without any iterative procedure so that its performance istime-saving compared with the Drude model and induced dipole model.展开更多
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11904036 and 12175081)Fundamental Research Funds for the Central Universities(Grant No.CCNU22QNOO4)。
文摘The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.
基金the National Natural Science Foundation of China(Grant Nos.11874242,11974216,and 11904210)Shandong Provincial Natural Science Foundation,China(Grant No.ZR2019MA056)Taishan Scholar Project of Shandong Province,China,and the China Postdoctoral Science Foundation(Grant No.2018M642689).
文摘To enhance the potential application of thermally activated delayed fluorescence(TADF)molecular materials,new functions are gradually cooperated to the TADF molecules.Aggregation induced emission can effectively solve the fluorescence quenching problem for TADF molecules in solid phase,thus aggregation-induced delayed fluorescence(AIDF)molecules were recently focused.Nevertheless,their luminescent mechanisms are not clear enough.In this work,excited state properties of an AIDF molecule DMF-BP-DMAC[reported in Chemistry-An Asian Journal 14828(2019)]are theoretically studied in tetrahydrofuran(THF)and solid phase.For consideration of surrounding environment,the polarizable continuum method(PCM)and the combined quantum mechanics and molecular mechanics(QM/MM)method were applied for solvent and solid phase,respectively.Due to the increase of the transition dipole moment and decrease of the energy difference between the first single excited state(S1)and the ground state(S0),the radiative rate is increased by about 2 orders of magnitude in solid phase.The energy dissipation of the non-radiative process from S1 to S0 is mainly contributed by low-frequency vibrational modes in solvent,and they can be effectively suppressed in aggregation,which may lead to a slow non-radiation process in solid phase.Both factors would induce enhanced luminescence efficiency of DMF-BP-DMAC in solid phase.Meanwhile,the small energy gap between S1 and triplet excited states results in high reverse intersystem crossing(RISC)rates in both solvent and solid phase.Therefore,TADF is confirmed in both phases.Aggregation significantly influences both the ISC and RISC processes and more RISC channels are involved in solid state.The enhanced delayed fluorescence should be induced by both the enhanced fluorescent efficiency and ISC efficiency.Our calculation provides a reasonable explanation for experimental measurements and helps one to better understand the luminescence mechanism of AIDF molecules.
基金Project (No. SR/FT/L-84/2003) supported by the Department of Science and Technology under the Science and Engineering Research Council Fast Track Scheme for Young Scientists, India
文摘Objective: To study the effect of halo substitution on disubstituted aryl semicarbazones on the anticonvulsant potential and model the activity based on quantum mechanics. Methods: A series of twenty-six compounds of N4-(4-bromo-3-methylphenyl) semicarbazones were synthesized and evaluated for the anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Some potential compounds were also tested in the subcutaneous strychnine (scSTY) and subcutaneous picrotoxin (scPIC) seizure threshold tests. The synthesized compounds were tested for behavioral impairment and CNS (central nervous system) depression in mice. Quantum mechanical modelling was carried out on these compounds to gain understanding on the structural features essential for activity. Results: Some compounds possessed broad spectrum anticonvulsant activity as indicated by their effect in pentylenetetrazole, strychnine, picrotoxin and maximal electro- shock seizures models in resemblance to other aryl semicarbazone derivatives reported earlier. The higher the difference in HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy levels was, the greater was the activity profile. Conclusion: The pharmacophoric requirements for compounds to exhibit anticonvulsant activity that includes one aryl unit in proximity to a hydrogen donor-acceptor domain and an electron donor have been justified with the molecular orbital surface analysis of the synthesized compounds.
文摘We used ABEEMon（atom-bond electronegativity equalization method） polarizable force field（ABEEMσπ PFF） method combined with QM and molecular dynamics-free energy perturbation（MD-FEP） methods to investigatethe function of water molecules in hydrolysis process of ImH[trans-Ru（Im）2Cl4]（ICR）. The activation free energiesobtained via MD-FEP calculation are in fair agreement with the experimental data. In addition, QM/MM（ABEEM）rationally describes the charge distributions and the electrostatic interaction between molecules. ABEEMσπ fluctua-ting charge model has the following good characteristics： （1） not only atomic charge regions but also σ,π bond andlone pair charge regions are explicitly represented for a molecule; （2） the region charges are geometry dependent andcalculated from time to time in the dynamic simulation without any iterative procedure so that its performance istime-saving compared with the Drude model and induced dipole model.
