-->PONE-D-24-47957-->-->Design of novel potent inhibitor based on 2D-QSAR of carbamate derivatives for AChE inhibition-->-->PLOS ONE

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Academic Editor

PLOS ONE

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Additional Editor Comments:

Authors have developed successfully validated QSAR model using dataset of 32 compounds. However, these count of dataset is very small? Further as per OECD guidelines authors need to divide these dataset into training set and test test. However, author have not provided any details statistical results differentiation for Training and Test set. Whether Internal validation was successful or not?

Also, After generating model, author can give detail analysis of impact of selected descriptor on biological activity considering functional groups/atoms and its importance to include SAR studies. This will further enhance quality of manuscript.

Authors have not used any standard drug for comparison of Molecular simulation and ADMET studies . I would suggest authors to add that also.

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Reviewers' comments:

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1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1:  The manuscript "Design of novel potent inhibitor based on 2D-QSAR of carbamate derivatives for AChE" has caught my attention. The study investigates how the lead molecule M6 interacts with the AChE protein with enhanced affinity. The results from QSAR and molecular simulations show that the chosen lead molecule could be a good compound to target against AChE. Overall, I found the manuscript interesting, but there are many flaws in it, from the introduction to the conclusion section. A more scientific perspective should guide the rewriting of the entire manuscript. Many paragraphs have more colloquial language.

• First, the abstract section mentions the compound as an AChE binder, but further clarification is required. Has a wet lab already validated it, or is it merely an in silico-based hypothesis? Regarding the docking score, the authors can give only a single digit instead of three digits (-11.200 kcal/mol). The abstract fails to mention the significance of the findings.

• In the introduction section:

• . The accumulation of these proteins kills these brain cells [9].---- Here, the authors have not mentioned any proteins that are associated with accumulation.

• The term 'in recent decades' is not appropriate in this context. Also, it should be mentioned firstly, secondly instead of second in the introduction section.

• Predictive pharmacokinetic analyses: typographical errors

• In the molecular docking section, the authors have mentioned that the downloaded crystal structure has a high resolution. However, the given value of 2.35 indicates a lower resolution. The manuscript does not mention the active site residues. Instead, the authors provide the coordinates. The authors need to provide the active site details of the protein for better understanding.

• The TIP3P should appear in upper case in the molecular dynamics section.

• In the molecular docking section “crystallized structure or be used as new leads." This sentence needs to be rewritten.

• The research was conducted using AutoDock Vina 4.2 [52]. The sentence needs to be reframed.

• 6. There are typographical errors, like residue. Additionally, figure 7, located adjacent to figure 6, should display residues instead of atoms. The authors can label the figures as Fig. 6(a) and Fig. 6(b) instead.

• According to the Rg report, the values (23.3 and 23) are negligible. The authors have stated that their interaction with M6 has resulted in a more tightly packed AChE. However, the given results contradict their statements. Here, an increase in the radius of gyration confirms that the protein has become less compact compared to its Apo form. There is no mention of these details in the manuscript.

• Hydrogen bond details: Here the authors do not do any comparison of the total hydrogen bonds between the apo and holo forms of the AChE protein. The authors have focused on the intermolecular hydrogen bond between the ligand and the protein. Instead, they have referred to it as intramolecular, which is incorrect.

• The manuscript does not mention the required residues associated with hydrogen bonds. This will provide a clear understanding of the consistency in the formation of hydrogen bonds between the protein and the ligand. Also, the authors have done a single run of the simulation instead of the triplicates. Two more simulation runs could better validate their findings.

• The manuscript needs to include the MM/PBSA score of the protein-ligand complex for improved validation of the protein-ligand complex interaction.

• Moreover, the author made no mention of the structural features of drug M6 and their functional group

• The manuscript can only be considered if the authors revise it as per the suggestions given above.

Reviewer #2:  The manuscript is very well written and has some new findings. There are some minor changes which I would like to suggest.

What is meant by M6 in the abstract?

There are some missing references throughout the manuscript.

In the section Principal Component analysis, the term correlation coefficient is not well described.

Also what is the coefficient of determination?

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Reviewer #1: Yes:  Dr.Selvaa Kumar C

Reviewer #2: No

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Design of novel potent inhibitor based on 2D-QSAR of carbamate derivatives for AChE inhibition

PONE-D-24-47957R1

Dear Dr. Chtita,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Sapan Kamleshkumar Shah, Ph.D., M.Pharm.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: