Computer-Aided Screening of Phytoconstituents from Ocimum tenuiflorum against Diabetes Mellitus Targeting DPP4 Inhibition: A Combination of Molecular Docking, Molecular Dynamics, and Pharmacokinetics Approaches

Round 1

Reviewer 1 Report

 

In this contribution, the authors reported a computational approach to assess the activities  of phytocompounds from Ocimum tenuiflorum against DPP-4. Different computational methods, such as molecular docking simulation, dynamics simulation and PK properties analysis were used for evaluation. Although these results are meaningful for further development of DPP-4 inhibitors by using these components, I do suggest to add/include some biological assay to verify the conclusions from such computational study. Some additional comments are listed below:

 

1.     Could you present chemical structure of the representative compounds from table 1? It will be easier for reader to catch up.

2.     For druglikeliness analysis, could you compare the results from the computational analysis and known/tested properties of Saxagliptin?

Author Response

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Reviewer 2 Report

The manuscript by the authors attempted to evaluate the mechanism of interaction between the phytoconstituents of Ocimum tenuiflorum and DPP4 in an in silico experimental model. While the concept looks worthy, several technical concerns need to be resolved.

The major specific reasons for my recommendation are:

1. The rationale for the choice of Linalool for MD simulation is unacceptable. One would have thought that compounds such as Dehydro-p-cymene with a better binding affinity and good interactions should have been considered but this was not the case.

2. Also, it is highly suggested that at least three compounds with good affinity towards DPP4 be subjected to MD simulation to have a more robust analysis of the compactness, flexibility and stability of the resulting complex in each case. Without this, the results as currently presented add no significant value to the existing body of knowledge and also not in agreement with the aim of the study.

3. There was no mention of how the docking was validated in the manuscript and this is recommended for inclusion.

4. The sequence length of DPP4 must be specified and information on its optimization for both docking and MD simulation must be included. Also, how were the ligands optimized before docking?

5. The editorials of the manuscript need to be improved for better quality.

Also be consistent in the reference citing, italicize scientific names and cite Tables and Figures at the appropriate sections of the manuscript.    

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Reviewer 3 Report

Its clearly that the manuscript has merit to be published in Molecules. The audience would like to see studies like this one. Diabetes is an emergency disease that must be prior study in silico to evaluate candidate molecules to inhibit protein linked to such disease.  According to the highlights and changes, it seems like the entire text was revised and improved. Therefore, the manuscript should be published the way it is.

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Reviewer 4 Report

This study aims to suggest  DPP4 inhibitor candidates from O. tenuiflorum phytocompounds via traditional in silico methods.

In my opinion, the following points can be considered.

1. 26 compounds are less for a database that can be virtually screened against a target unless it is an in-house database and experimental validation is included in the study.

2. Figure 2 should be clear as the residue labels are not visible in many cases. Figure 2's legend should also explain the type of interactions along with color and all kinds of representations.

3. Docking poses can also be selected based on more than one algorithm and rescoring with other methods.

4. Since some experimentally proven DPP4 inhibitors are available, common pharmacophore features can also be revealed.

5. Since the binding energy is comparable with the positive control, it is fine to consider the compounds as candidates, however I recommend including the experimental results.

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Round 2

Reviewer 1 Report

Without results from a proper biological assay as control/confirmation, I am unable to recommend publication of this manuscript.

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Reviewer 2 Report

The manuscript has been improved with most suggestions considered and incorporated. However, some technical concerns still need to be addressed:

1. The presentation of Figure 4 is not consistent and makes it difficult to follow all the parameters evaluated as they have been presented in different time unit. It is strongly suggested that either 'ns' or 'ps' be used consistently for Figures 4A, B, C and E.

2. Tables should rather present the average values for RMSD, Rg, RMSF and SASA, instead of ranges as currently presented. The units should also not be repeated on the Table but rather be across the first row for each parameter.

3. Improve on the consistency of intext referencing e.g Sutton et al. (2012) [16],  Patil et al. (2021) [22] etc must be harmonized.

4. it could also be good to see comparison between the interaction plots for the three simulated compounds and the standard before and after MD simulation. This is needed to ascertain if some interactions were conserved/maintained throughout the simulation period.  

Author Response

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