A series of inhibitors for anti-apoptotic Bcl-2 proteins based on BHI-1 were synthesized and their binding interactions with Bcl-2, Bcl-X L , and Bcl-w were evaluated. It was found that modification of BHI-1 resulted in varied binding profiles among Bcl-2, Bcl-X L , and Bcl-w and a set of inhibitors with varied selectivity to Bcl-2, Bcl-X L , and Bcl-w protein have been identified. Molecular modeling of the interaction of the BHI-1 based analogs with the anti-apoptotic Bcl-2 proteins suggested that the binding site for the BHI-1 based inhibitor was the least conserved section among Bcl-2, Bcl-X L , and Bcl-w: targeting the non-conserved section may account for the observed selectivity of the BHI-1 based inhibitors among the anti-apoptotic Bcl-2 proteins. The validity of the model was supported by a strong correlation between the model-calculated binding energy and the experimental binding affinity. In summary, our studies suggest that most of the reported inhibitors for antiapoptotic Bcl-2 proteins are nonselective and BHI-1 is a promising template to distinguish among Bcl-2, Bcl-X L , and Bcl-w by targeting the nonconserved domain among the anti-apoptotic Bcl-2 proteins. Molecular-modeling aided rational development of BHI-1 based selective inhibitor for antiapoptotic Bcl-2 proteins is underway.
A limited number of studies with low risk of bias were available to address the antimicrobial efficacy of CHX-V on MS in patients during orthodontic treatment with fixed appliances. Therefore, while the majority of studies found CHX-V to be an effective antimicrobial against MS at an interval of 3-4 weeks, the strength of the recommendation is weak. Longitudinal studies are needed to determine whether this antimicrobial effect will contribute to clinically significant caries reduction in patients undergoing orthodontic treatment with fixed appliances.
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