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Reviewer #1: Ursolic acid(UA), the derivative of oleanolic acid, is widely studied due to numerous pharmacological activities. The author had synthesized a series of ursolic acid derivatives, which is a break ground result. In this paper, simulation approach is employed to explore the effects of binding affinity for inhibitory activities, which is an innovative work for the study on anti-diabetic properties of the hydrolyzation analogues of UA.
While, in order to verify that simulation model can explain the experimental results, some work needs to be complemented
Major Issues:
1. In the section of ¡°structure activity relationship¡±
The author had got the value of IC50 by experiments, and calculated the binding energy to understand the relationship between binding mode and bioactivity. While Quantitative Structure-Activity and Relationships (QSAR) is the only persuasive tool to explain which structures play the important role in enhancing the inhibition activity.
In order to increase the confidence level of simulation results, the author has to demonstrate the QSAR equations to support their conclusions. The math expression of QSAR equation can be obtained by regression analysis. Only after the regression analysis work is completed, we can know which site in UA plays the important role for inhibition activity.
2. In the section of ¡°molecular docking mode¡±, the author only listed the calculation results, but no parameter settings. The author has to list the major parameters, such as which kind of force field, which algorithm were used
Minor Issues:
3. Typo: In Figure 1. 3a - 8a & 3b ¨C 8b should be replaced by 3a - 10a & 3b ¨C 10b
4. Use idiomatic English expression:
Line 1: November 14 ---> November 14th;
Line 29: Expose
5. Some abbreviate needs full name, such as: Line 92: DMSO

Reviewer #2: This manuscript reports the synthesis and evaluation of a group of ursolic acid derivatives for anti-diabetic applications. The authors presented in vitro anti-diabetic activity and modeling studies to demonstrate their structure-bioactivity relationships, which would be useful for developing more effective alpha-glucosidase inhibitors. The manuscript is also well-written. I would recommend an acceptance in PLOS One after minor revisions.
1. The authors need to discuss what are the rationals of the overall molecular structure design and what are the objectives and hypotheses between each group analysis for molecules of interest.
2. It would be helpful if the authors can briefly discuss about the control (Acarbose) selection, since there are so many available inhibitors out there.
3. In the caption of Fig. 4, "liphilic" should be "Lipophilic". The authors need to carefully check over the manuscript to avoid typos.
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