Screening of small molecule inhibitors targeting DNA polymerase η
The repair of DNA damage and maintenance of genomic stability are essential for the normal growth and adverse defense of plants and animals.In view of the genomic instability caused by the misincorporation of DNA polymerase,this study took DNA polymerase η as the research object and screened its possible small molecule inhibitors by computational simulated molecular docking and detected their enzyme kinetic parameters.The results showed that deoxyadenosine triphosphate(dATP)had an inhibitory effect on the activity of DNA polymerase η,resulting in a relative extension efficiency of 36%to 42%.Simulated molecular docking and in vitro experimental results showed that cyclic GMP-AMP(cGAMP)had a lower binding energy(with an affinity of-35.1 kJ/mol)than dATP(with an affinity of-26.7 kJ/mol)to DNA polymerase η.Enzyme kinetic experiments also showed that cGAMP had a stronger inhibitory ability than dATP and achieved the maximum effect at the concentration of 0.5 mmol/L(with a relative extension efficiency of 13%).Therefore,a potential small molecule inhibitor targeting DNA polymerase η was screened out in this study.At the same time,in view of the tolerance to antitumor drug(DNA damage agent)caused by high expression of this protein,these results provide a basis for the development of new drugs.
repair of DNA damageDNA polymeraseenzyme kineticscomputational biologycyclic GMP-AMP(cGAMP)
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维普
