QSAR Insights into Antidiabetic Activity of Natural Sulfur-Containing Compounds

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Summary

This review manuscript summarizes the antidiabetic potential of sulfur-containing natural compounds, with a particular emphasis on thiosugars derived from Salacia species and additional sulfur-containing compounds such as organosulfur sulfides and sulfur hopanes. The manuscript integrates phytochemical data, traditional medicinal use, pharmacological effects, and computational QSAR/PASS predictions.

The topic is relevant to the field of natural product pharmacology and diabetes research, particularly regarding α-glucosidase inhibitors and natural antidiabetic scaffolds. The manuscript provides an extensive compilation of compounds and predicted biological activities.

However, some aspects require improvement before publication. Although the manuscript refers to QSAR/PASS predictions, the methodology used for these predictions is not clearly described. The authors should specify the software, parameters, thresholds (e.g., Pa/Pi values), and criteria used for activity prediction. Additionally, the structure, scientific depth, and clarity of the discussion should be improved. Some sections appear overly general and not directly linked to diabetes pharmacology.

Minor Comments

Title: The title is appropriate but slightly broad. Consider specifying the focus on Salacia thiosugars and sulfur natural products.

Abstract: The abstract is informative but somewhat long. Lines 24–38 introduce sulfur hopanes, which may distract from the primary focus on antidiabetic compounds. Consider shortening this section.

Keywords: Current keywords (Line 52): Antidiabetic; α-glucosidase; inhibitors; sulfur-containing; products

Consider adding: Salacia, thiosugars, QSAR, natural products

Introduction: The introduction is clear but could benefit from: quantitative epidemiological data on type 2 diabetes prevalence, and references to current pharmacotherapy limitations (Relevant section: Lines 56–63.)

Section organization: Section titles should be made more consistent with the main theme of the manuscript. For example: Section 2: “Distribution of polysulfides in plants and their activity”. This title suggests general phytochemistry rather than antidiabetic pharmacology.

References: Ensure that references supporting pharmacological activity are primary experimental studies, not only reviews.

Main Comments

1. Insufficient methodological explanation of QSAR/PASS analysis

The manuscript frequently refers to PASS-based QSAR predictions, yet the methodological description is insufficient.

The authors should clearly describe:

• the PASS software version
• the training datasets
• Pa / Pi thresholds used
• validation strategy
• reliability or limitations of predictions

Without these details, the predictive conclusions lack transparency.

Relevant sections:
Lines 40–48, 149–154, and other QSAR-related parts of the manuscript.

2. Lack of critical discussion of predicted biological activity

The review largely presents predicted activities without critical interpretation.

For example, sulfur hopanes are discussed as potential antidiabetic agents (Lines: 30–38), yet these molecules are primarily known as geochemical biomarkers rather than pharmacologically validated compounds.

The authors should discuss: the biological plausibility, structural features linked to antidiabetic activity, and comparison with known α-glucosidase inhibitors (e.g., acarbose, miglitol, voglibose).

Currently, the manuscript gives the impression that predicted activities are equivalent to experimentally validated pharmacology.

3. Limited discussion of clinical relevance

Although Salacia extracts are mentioned as traditional antidiabetic agents, the review lacks discussion of: clinical studies, pharmacokinetics, safety, dosage forms, and human efficacy. Adding this perspective would significantly increase the translational value of the review.

4. Figures and structure-activity analysis

The manuscript includes compound descriptions but provides limited discussion of structure–activity relationships.

For example, for compounds such as: salacinol, neosalacinol, kotalanol.

The review would benefit from discussion of: sulfonium group importance, sugar ring modifications, and stereochemistry effects. This would align better with the stated QSAR focus.

Comments on the Quality of English Language

The English language is generally understandable but requires minor editing for clarity and flow. Examples: line 166–167: “1-Ethyl-3-methyl trisulfide (1, or 2,3,4-trithiahexane...)” The sentence could be simplified.

Several sections contain overly long sentences that should be split for readability.

Author Response

Reviewer 1

Response to Reviewer

We sincerely thank the reviewer for the careful evaluation of our manuscript and for the constructive comments and suggestions. These comments have significantly helped us improve the clarity, structure, and scientific depth of the manuscript. All changes have been incorporated into the revised version of the manuscript, and the text has been edited accordingly. Our detailed responses to each comment are provided below.

 

General Comment

Reviewer comment:
This review manuscript summarizes the antidiabetic potential of sulfur-containing natural compounds, with particular emphasis on thiosugars derived from Salacia species and additional sulfur-containing compounds such as organosulfur sulfides and sulfur hopanes. The manuscript integrates phytochemical data, traditional medicinal use, pharmacological effects, and computational QSAR/PASS predictions. The topic is relevant; however, some aspects require improvement, including clearer explanation of QSAR/PASS methodology and improvement in structure and discussion.

Response:
We thank the reviewer for recognizing the relevance of our topic and the comprehensive nature of the compiled data. In the revised manuscript, we have improved the methodological description of the PASS-based QSAR predictions, expanded the discussion of the pharmacological plausibility of predicted activities, and strengthened the structure and clarity of several sections to better connect them with antidiabetic pharmacology.

 

Minor Comments

Title

Reviewer comment:
The title is appropriate but slightly broad. Consider specifying the focus on Salacia thiosugars and sulfur natural products.

Response:
We appreciate this suggestion. The title has been revised to better reflect the main focus of the review. The new title emphasizes sulfur-containing natural products and thiosugars from Salacia species while retaining the broader relevance to antidiabetic compounds.

 

Abstract

Reviewer comment:
The abstract is informative but somewhat long. Lines 24–38 introduce sulfur hopanes, which may distract from the primary focus.

Response:
The abstract has been shortened and reorganized to emphasize the main focus on antidiabetic sulfur-containing natural products, particularly thiosugars from Salacia. The section discussing sulfur hopanes has been condensed to avoid distracting from the primary theme.

 

Keywords

Reviewer comment:
Consider adding: Salacia, thiosugars, QSAR, natural products.

Response:
The keywords have been revised accordingly. The following keywords have been added:
Salacia; thiosugars; QSAR; natural products.

 

Introduction

Reviewer comment:
The introduction could benefit from quantitative epidemiological data on type 2 diabetes prevalence and references to current pharmacotherapy limitations.

Response:
We have expanded the Introduction to include recent epidemiological data on the global prevalence of type 2 diabetes and added references discussing limitations of current pharmacotherapy, including adverse effects and limited long-term efficacy of some synthetic α-glucosidase inhibitors.

 

Section Organization

Reviewer comment:
Section titles should be more consistent with the main theme.

Response:
Section titles have been revised to more clearly reflect the antidiabetic pharmacological focus. For example, sections discussing sulfur-containing phytochemicals now emphasize their potential antidiabetic activity and relevance to α-glucosidase inhibition, rather than presenting them solely from a phytochemical perspective.

 

References

Reviewer comment:
Ensure that references supporting pharmacological activity are primary experimental studies.

Response:
We have carefully reviewed the reference list and added additional primary experimental studies where pharmacological activity is discussed. Several review-only citations have been replaced or supplemented with original experimental literature.

 

Main Comments

1. Insufficient methodological explanation of QSAR/PASS analysis

Reviewer comment:
The manuscript refers to PASS-based QSAR predictions, yet the methodological description is insufficient.

Response:
We thank the reviewer for highlighting this important point. The revised manuscript now includes a dedicated subsection describing the PASS-based QSAR methodology. Specifically, we have added:

• The PASS software version used for prediction
• A brief description of the training datasets used by PASS
• The probability thresholds (Pa/Pi values) applied for activity interpretation
• The criteria used to identify reliable predicted activities
• A short discussion of limitations and predictive reliability

This information has been added to the sections corresponding to Lines 40–48 and 149–154 in the revised manuscript.

 

2. Lack of critical discussion of predicted biological activity

Reviewer comment:
Predicted activities are presented without sufficient critical interpretation, particularly regarding sulfur hopanes.

Response:
We agree with the reviewer and have revised the relevant sections to clarify that PASS predictions represent computational hypotheses rather than experimentally confirmed activities. Additional discussion has been added addressing:

• Structural features that may support antidiabetic activity
• Comparison with known α-glucosidase inhibitors such as acarbose, miglitol, and voglibose
• The limited pharmacological validation of compounds such as sulfur hopanes

This revision emphasizes that computational predictions should guide future experimental studies rather than be interpreted as confirmed pharmacological effects.

 

3. Limited discussion of clinical relevance

Reviewer comment:
The review lacks discussion of clinical studies, pharmacokinetics, safety, and human efficacy of Salacia extracts.

Response:
A new subsection has been added discussing:

• Clinical studies involving Salacia extracts
• Reported human antidiabetic effects
• Safety and tolerability data
• Pharmacokinetic considerations and dosage forms

These additions improve the translational perspective of the review.

 

4. Figures and structure–activity analysis

Reviewer comment:
More discussion of structure–activity relationships is needed.

Response:
We have expanded the structure–activity relationship (SAR) discussion for key compounds including salacinol, neosalacinol, and kotalanol. The revised text now discusses:

• The role of the sulfonium group
• Importance of sugar ring configuration
• Effects of stereochemistry
• Structural similarities with known α-glucosidase inhibitors

These additions strengthen the connection between the chemical structures and their predicted or known pharmacological activities.

 

Comments on the Quality of English Language

Reviewer comment:
The English language requires minor editing for clarity.

Response:
The manuscript has been carefully edited to improve clarity, grammar, and readability. Several long sentences have been simplified, including the sentence noted in Lines 166–167. Overall, the text has been revised to improve scientific flow and readability.

 

Final Statement

We sincerely thank the reviewer for their thoughtful and constructive comments. The revisions have significantly improved the manuscript's clarity, methodological transparency, and scientific depth. We hope the revised version meets the reviewer’s expectations and we greatly appreciate their valuable input.

 

All abbreviations, additions and corrections are highlighted in blue.

 

Valery M Dembitsky

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

I would like to thank the editors for entrusting me with the review of this review.

I do not have a favorable opinion of this work, as it contains factual errors and numerous editorial mistakes. The authors are inconsistent in their use of abbreviations and symbols for specific issues. I understand that the work is very extensive, which makes it difficult to prepare it correctly. However, if the authors undertook to prepare such an extensive review, they are also obliged to maintain quality throughout the text.

The most disturbing thing is the incorrect name of the compound described under number 2. This is because it is 1,3-diethyl trisulfide, and not as the authors state 1,3-dimethyl trisulfide.

The text contains a description (which appears to be incorrectly worded) of Table 0, but no table is included at this point.

In the figures showing the structure of the compounds, the names are given for some of them, but not for most. Please include these names consistently in the figures or in the figure captions, consistently throughout the entire work. The figure captions include interpretations of the effects of these compounds, which seems unnecessary here, as the effects of each compound are discussed extensively in the text.

It is unclear why Latin names are given for most plant materials, but not for some (e.g., shallots) (lines 82, 139, and subsequent). I also do not know whether it is necessary to give both names (common and Latin) each time these species are mentioned. Perhaps it would be better to give all names (common and Latin) in the first place where the raw materials are mentioned, and then use only one name for each raw material.

Abbreviations for compound names have been introduced for several raw materials (e.g., DMTS, line 128; DATS, line 249), while later on, the full name or abbreviation was used interchangeably.  I suggest either abandoning abbreviations for compound names or introducing such abbreviations for all names and using them consistently.

From line 293 onwards, the term “trisulphane” is used. It is unclear which compound the authors are referring to when using this name.

Another problem is the use of abbreviations without explaining their meaning. QSAR and PAAS appear as early as line 24, where there is no explanation of the meaning of these abbreviations. Similarly, Pa and Pi, used repeatedly in the text, are explained in lines 1358–1359, and how to interpret these values is explained in lines 297–302. I suggest explaining the meaning and interpretation of this data in the first place where these abbreviations and data are presented.

Cluster analyses have been labeled in different ways (lines: 207–233; 305–325; 838–886). These labels should be corrected.

The way in which the text refers to elements in the figures showing the structures of compounds is unclear. Each reference should be presented consistently as a reference to the figure and the structure number, e.g., according to the formula: (Figure 1, structure 2).

In several places, the text is bolded or written in a different font (lines 400-411; 821-824; 1053-1056; 1083-1084). This is incomprehensible to me and needs to be corrected.

I do not understand why GC-MS chromatograms are presented for one of the compounds discussed, since the paper concerns the usefulness of these compounds and their pharmacodynamic effects.

There are also many minor editorial errors:

Line 503: 1. ,4-Diallyltetrasulfane instead of 1,4-Diallyltetrasulfane

Line 509: no square bracket [ indicating the beginning of references

Line 881: there is point 3) but there are no points 1) and 2) before it

Lines 424-425: markings (i) Garlic and (i) Onion (it should be (ii) here)

I also suggest introducing a list of abbreviations used in the paper.

The work is very extensive. I would also suggest that the authors consider whether they see any possibility of shortening it, which would make it easier for readers to understand.

Author Response

Reviewer 2

 

Response to Reviewer 2

We sincerely thank the reviewer for the careful reading of our manuscript and for the detailed comments. We appreciate the time and effort invested in evaluating this extensive review. The reviewer’s remarks were extremely helpful in improving the clarity, consistency, and overall quality of the manuscript. All issues raised have been carefully addressed in the revised version, and the manuscript has been thoroughly edited for accuracy, consistency, and readability. Our responses to the specific comments are provided below.

 

Comment 1.
The manuscript contains factual errors, editorial mistakes, and inconsistent use of abbreviations and symbols.

Response:
We appreciate this important observation. The entire manuscript has now been carefully re-examined and thoroughly edited to eliminate editorial inconsistencies, typographical errors, and formatting issues. Abbreviations, compound names, and symbols have been standardized throughout the text. In addition, the manuscript was carefully proofread to ensure consistency in terminology, formatting, and scientific notation.

 

Comment 2.
Incorrect name of compound number 2 (should be 1,3-diethyl trisulfide instead of 1,3-dimethyl trisulfide).

Response:
We thank the reviewer for identifying this error. The compound name has been corrected to 1,3-diethyl trisulfide in the revised manuscript, and the corresponding description, structure labeling, and figure references have been updated accordingly.

 

Comment 3.
The text refers to “Table 0,” but no such table exists.

Response:
We agree with the reviewer. The reference to Table 0 resulted from an editing oversight. This incorrect reference has been removed, and the text has been corrected accordingly.

 

Comment 4.
Compound names are included in some figures but not others. Names should be consistently included either in figures or captions.

Response:
All figures have been revised to ensure consistent labeling of compound names and structure numbers. Compound names are now systematically provided either within the figure or in the corresponding figure captions to ensure clarity and uniformity throughout the manuscript.

 

Comment 5.
Figure captions include interpretations of biological effects, which may be unnecessary.

Response:
We agree with this suggestion. Figure captions have been shortened and simplified, and explanatory interpretations have been moved to the main text where appropriate.

 

Comment 6.
Inconsistent use of Latin and common plant names.

Response:
This issue has been corrected. In the revised manuscript, both Latin and common names are provided at their first occurrence, and thereafter only the Latin name is used consistently throughout the text.

 

Comment 7.
Inconsistent use of abbreviations for compound names (e.g., DMTS, DATS).

Response:
Following the reviewer’s suggestion, abbreviations for compound names have been standardized and used consistently throughout the manuscript. Each abbreviation is now clearly defined at its first appearance in the text.

 

Comment 8.
The term “trisulphane” (line ~293) is unclear.

Response:
The terminology has been clarified in the revised manuscript. The term “trisulfane” is now explicitly defined when first introduced, and where necessary it has been replaced with the specific compound name to avoid ambiguity.

 

Comment 9.
Abbreviations (QSAR, PASS, Pa, Pi) are introduced without explanation.

Response:
We thank the reviewer for highlighting this issue. All abbreviations are now defined at their first occurrence, including QSAR (Quantitative Structure–Activity Relationship), PASS (Prediction of Activity Spectra for Substances), Pa (probability of activity), and Pi (probability of inactivity). In addition, a brief explanation of the interpretation of Pa and Pi values has been moved to the first section where PASS predictions are introduced.

 

Comment 10.
Cluster analyses are labeled inconsistently.

Response:
The terminology used to describe activity clusters has been standardized throughout the manuscript. All cluster analyses are now presented in a consistent format and labeling system.

 

Comment 11.
References to structures in figures are unclear.

Response:
All references to chemical structures have been standardized according to the reviewer’s recommendation. Structures are now consistently cited using the format:
(Figure X, structure Y).

 

Comment 12.
Bold text or different fonts appear in several parts of the manuscript.

Response:
These formatting inconsistencies were unintentional. All such formatting issues have been removed or standardized, and the manuscript now uses a uniform font and formatting style throughout.

 

Comment 13.
GC–MS chromatograms are included although the manuscript focuses on biological activity.

Response:
We appreciate this comment. The chromatographic figure was originally included to illustrate the analytical identification of certain sulfur compounds. However, to maintain focus on biological activity and pharmacological relevance, the GC–MS chromatogram has been removed from the revised manuscript.

 

Comment 14. Minor editorial corrections

• Line 503: corrected to 1,4-Diallyltetrasulfane.
• Line 509: missing reference bracket added.
• Line 881: numbering corrected.
• Lines 424–425: corrected enumeration (i), (ii), etc.

All minor typographical and editorial errors identified by the reviewer have been corrected.

 

Comment 15.
Suggestion to introduce a list of abbreviations.

Response:
A List of Abbreviations has now been added to the manuscript to improve readability.

 

Comment 16.
The manuscript is very extensive and could potentially be shortened.

Response:
We appreciate this suggestion. Several sections have been edited and condensed, figure captions shortened, and redundant descriptions removed. These revisions have improved the readability of the manuscript while preserving the scientific completeness of the review.

 

Final remark

We sincerely thank the reviewer for the constructive criticism, which significantly improved the clarity, consistency, and scientific quality of the manuscript. All comments have been carefully addressed, and the revised version reflects these improvements.

 

All abbreviations, additions and corrections are highlighted in blue.

 

Valery M Dembitsky

 

 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript "QSAR  Insight into Antidiabetic Activity of Natural Sulfur-Containing Compounds"needs improvement in terms of organization.

General comments

• The introduction is subjective and general, especially regarding the species and genera of plants addressed in the manuscript. The genus Salacia is detailed in the introduction and there is nothing specified about the genus Allium and the Cistus ladanifer species, given that more than half of the manuscript details these species. The question is what was the purpose of the study? research only on the Salacia genus?
• After the introduction, the chapter materials and methods should be includes, respectively chapter 4 of the manuscript pg.34
• In the chapter 2 of the manuscript, the subchapters on plant genera can be made-for better organization of the information.

Specific comments

• Under table 1 it should be specified what the first column represents and the notes should also be entered in the text.
• Line- 653-657 – what table is and where is?
• 2 – why are working conditions and methods listed in the annotations?
• Fig 3, 4, 5, 6, - same aspects- pharmacological activities, chemical composition are added to footnotes. – please correct
• All the names of the specie must be written in italics – please verify and correct in all the manuscript.

Author Response

Reviewer 3

Response to Reviewer 3

We sincerely thank the reviewer for the careful evaluation of our manuscript entitled “QSAR Insight into Antidiabetic Activity of Natural Sulfur-Containing Compounds.” We appreciate the constructive comments regarding the organization and clarity of the manuscript. Following the reviewer’s suggestions, the manuscript has been substantially revised to improve structure, readability, and consistency. Our responses to each comment are provided below.

 

General Comments

Comment 1

The introduction is subjective and general. The genus Salacia is discussed in detail, while the genus Allium and the species Cistus ladanifer are not adequately introduced, although they are discussed extensively later in the manuscript. The purpose of the study is therefore unclear.

Response:
We thank the reviewer for this important observation. The Introduction has been revised and expanded to better reflect the overall scope of the manuscript. In the revised version, we now provide balanced background information on the three principal biological sources discussed in the review:

• the genus Salacia (thiosugar antidiabetic compounds),
• the genus Allium (organosulfur sulfides and polysulfides), and
• the species Cistus ladanifer (sulfur-containing terpenoid derivatives).

In addition, the aim and scope of the study are now explicitly stated at the end of the Introduction. The revised text clarifies that the purpose of the work is to analyze the potential antidiabetic activity of structurally diverse sulfur-containing natural products using QSAR/PASS prediction methods, integrating compounds from plant, microbial, and sedimentary sources.

 

Comment 2

After the introduction, a Materials and Methods chapter should be included (currently Chapter 4, p.34).

Response:
We agree with the reviewer that the methodological section should appear earlier in the manuscript. In the revised version, the Materials and Methods section has been moved directly after the Introduction to improve logical flow and allow readers to understand the computational methodology before the discussion of the predicted activities.

 

Comment 3

In Chapter 2, subchapters on plant genera should be created for better organization.

Response:
Following this suggestion, Chapter 2 has been reorganized into clearly defined subsections according to biological source and compound class. The revised structure now includes subsections such as:

• Sulfur-containing compounds from the genus Allium
• Thiosugar derivatives from the genus Salacia
• Sulfur-containing metabolites from Cistus ladanifer
• Sedimentary sulfur compounds and hopanes

This restructuring significantly improves the organization and readability of the manuscript.

 

Specific Comments

Comment 4

Under Table 1 it should be specified what the first column represents, and the notes should also be entered in the text.

Response:
The description of Table 1 has been revised. The first column is now clearly defined in the table caption, and explanatory notes have also been incorporated into the corresponding text section for clarity.

 

Comment 5

Lines 653–657 – what table is this and where is it?

Response:
We thank the reviewer for pointing out this oversight. The text in lines 653–657 contained an incorrect table reference resulting from earlier editing. This has been corrected, and the appropriate table reference is now clearly indicated in the revised manuscript.

 

Comment 6

Why are working conditions and methods listed in the annotations?

Response:
We agree that methodological details should not be placed in figure or table annotations. In the revised manuscript, experimental and computational details have been transferred to the Materials and Methods section, and figure/table annotations have been simplified accordingly.

 

Comment 7

Figures 3–6 contain pharmacological activities and chemical composition in the footnotes.

Response:
Following the reviewer’s suggestion, figure captions have been shortened and simplified. Interpretative descriptions of pharmacological activities have been moved from figure captions to the main text, where they can be discussed more appropriately.

 

Comment 8

All species names must be written in italics.

Response:
This issue has been carefully corrected throughout the manuscript. All scientific names of plant species and genera are now consistently formatted in italics according to standard taxonomic conventions.

 

Final remark

We greatly appreciate the reviewer’s constructive comments, which helped us significantly improve the organization, clarity, and scientific presentation of the manuscript. The revised version now presents a clearer structure, improved methodological transparency, and consistent formatting throughout.

Thank you again for your valuable suggestions.

 

All abbreviations, additions and corrections are highlighted in blue.

 

Valery M Dembitsky

 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript was extensively revised by authors and was improved considerably, according to the recommendations. The manuscript is now suitable for publication.

Author Response

Response to Reviewer 1

We sincerely thank the reviewer for the careful evaluation of our revised manuscript and for recognizing the improvements made in response to the previous comments. We greatly appreciate the reviewer’s positive assessment and are pleased that the manuscript is now considered suitable for publication.

Sincerely yours

 

Valery Dembitsky

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

All species names must be written in italics -please check especially at the modified parts level.

Once again regarding figure annotations. These should not contain details about methodology or discussion - these aspects can be detailed in the text not under the images or figures.

Author Response

Response to Reviewer 2

We thank the reviewer for these helpful and precise comments.

1. Italicization of species names:
   All species names throughout the manuscript, including those in the revised sections, have been carefully checked and corrected to ensure consistent formatting in italics.
2. Figure annotations:
   We agree with the reviewer’s suggestion. All figure annotations have been revised to remove methodological and discussion-related details. These aspects have been relocated to the main text, and the figure captions have been streamlined to include only essential descriptive information.

We appreciate the reviewer’s comments, which have helped improve the clarity and presentation of the manuscript.

Sincerely yours

 

Valery M. Dembitsky