Overall this manuscript contains important supportive information consistent with the premise that these two common food additives (spices) contribute (or not so much in the case of CAL extract) inhibition of digestive enzyme activity; particularly in the case of ZBM. I thought the rationale of the premise underlying this work was well discussed.

Overall, I only have one major concern in this work and that is I think some information that related the concentrations used (both of the extracts and the purified molecules) to that commonly found when added to food. I would guess the common reader (including myself) really have no idea how to relate these finding to actual usage. I think including this information is critical to publishing this work such that it would be most meaningful.

I have a few lesser concerns as follows:

1) Explain glide scores and meaningfulness of them. The reader needs context. What is considered a score indicative of high affinity? What is a poor score (for example what is the score for the next likely interaction site of rutin with lipase); any significance to a score of 6 vs 8? etc.

I also have a few suggestions for improvement of the manuscript.

1) Line 21, abstract, change to “Catechin had no detectible inhibition …”
2) Line 29, abstract, change elucidated to “suggested”
3) Line31, abstract, I don’t understand what “proper concentrations” mean. Perhaps optimal or “defined ratios” ? or is this referring to that found in a “conventional diet” ? or at concentrations typically found in diets?
4) Bottom of page 3; (introduction): I think the review in Int J Mol Sci (18,10:2172) by Zhang et al , 2017 would be a good citation for explaining the components found in Zanthoxylum. I found it very helpful.
5) P. 4, line 78-79, Do the authors have estimates of [capsaicin] and [sanshool] in these crude extracts? Or even typical values, or ranges ?
6) P. 5, lines 80-85, Provide basic information for all of these compounds used in this manuscript. For example the pharmaceuticals acarbose and orlistat, which are used as positive controls, are directed toward inhibiting the appropriate enzymes.
7) P.5, line 88, change frutification to “fruits”.
8) P.5, line 89-91, it is not clear how the pre-treatment was done. The way it is written suggests the dry powders were sonicated (which I would be sure it was not). Please correct.
9) P.5, perhaps it would be useful to provide a rational for why the pH for the various assays was chosen. I don’t understand why there were NOT performed at a pH likely present in their biological location (stomach)?? What are pH optimum for these enzymes?, Also when first mentioned it should be reemphasized that amylase is the gastric version (not the salivary enzyme which would have different properties).
10) P.6, line 107, “I“ was not defined.
11) P. 6., line 114-117. It is not clear what ESC was and how it was obtained, more explanation would be helpful here.
12) P.6, line 215, not sure what “set” means. Perhaps this sentence could read “Stock concentrations of …….. were 30 U/mL and 0.5 U/ml, respectively” (cite appropriate figure).
13) P.7, line 133, not sure that “harmonized“ is the correct word here.
14) P.9, line 168 should read, pancreatic lipase inhibitory “activity” was observed ….
15) P.9, line 168-175, This section would make more sense if acarbose and orlistat were explained earlier (as noted above in comment # 6). Alternatively, an explanation in this location in the manuscript could substitute for an explanation in the introduction as suggested in #6.
16) P. 10, line line 188, I think this synergistic effect should be characterized as a “modest” synergestic interaction.
17) P.11, line 208-210, How does one explain the strong effect of ZBM on the lipase but minimal impact with sanshool? What are other components in ZBM that could account for this strong inhibition?, Also since ZBM is a crude extract it suggests something is present which is even more effective than orlistat
18) p. 11, line213, change a non recordable inhibition to “no inhibition”.
19) I would prefer the figure 2., a, b, to be actually labeled in the figure (Lipase, Amylase) rather than in the fig legend.
20) As above, it would much easier for the reader to have a-j, actually labeled on the figure (example, Figure 3a, would be labeled: ZBM:lipase)
21) P.16, and following; discussion of interactions; what is the significance of all three inhibitors sharing target sites in similar region (the “hinge”?) even though their molecular interactions are quite different. Is there a significance to those regions relative to known functional mechanisms of those enzymes? Are these the substrate binding sites, for example? Or known regulatory sites, etc.
22) P.17, line 330-332, This sentence in poorly constructed and needs to be fixed.
23) P. 29, 333, and following. It is also suggested that these assays were performed under gastric conditions. What parameters were changed compared to previous assays? Fig S1 in the supplemental conditions indicates the pH was still close to neutrality (pH 6.9, page 26, line 53) or pH 8 (p. 26, line 15) instead of under acid conditions!!
24) Figure S1, it is not clear what control vs digested means (does it mean simulated digestion conditions?).

One concern in this work is: I think some information relating the concentrations used (both of the extracts and the purified molecules) to that commonly found when added to food. I would guess the common reader (including myself) really have no idea how to relate these finding to actual usage. I think including this information is critical to publishing this work such that it would be most meaningful. What I am getting at is; are these concentrations within the range of possible ingestion under “normal” conditions? For example would ZBM applied to food be expected to be in range of 80 to 130 ug/mL and that of CAL be in range of 500- 1167 ug/ml. in food? These are the IC50s ranges for lipase and amylase.

Another comment: Lines 361-363 Simulated gastric conditions are not described anywhere. How was pepsin digest performed, pH optimum is around pH 2 ? was pH readjusted back to 6.9 and 8.0 for the enzyme assays? How? Was pepsin-treatment the ONLY simulation, if so; this section should be called pepsin-treatment (digest) not gastric simulation. (say for example, "in a attempt simulate gastric conditions the extract was treated with pepsin")