In Silico Prediction, Characterization and Molecular Docking Studies on New Benzamide Derivatives

Round 1

Reviewer 1 Report

In this work, the evaluated candidates were exposed to in silico approaches–molecular docking studies and the measurement of QSAR properties, in order to corelate the drug design with their level of permeability. The chemical compounds 1c, 1d, and 1n stand out from the other compounds in the series, through their favourable molecular properties that make them suitable candidates for active ingredients with oral administration. This work is meaningful and I think it can be published. Meanwhile, some issues need to be improved before publication in the following:

In Molecular docking part: The region of ligand docking is important. Therefore, the authors must provide in detail of its position of docking, whether it is the binding pocket or the whole protein. And also criteria of docking evaluation, such as their docking scores or binding affinities and docking results are required to provide as evidence to make it clear.

Line 396, 1a-o should be 1a-1o.

All tables should use three line grids.

All calculation methods should have a detailed description process, at least in SI.

Author Response

Please see the attachmant

Author Response File: Author Response.pdf

Reviewer 2 Report

In the present study, authors have used the molecular docking technique to investigate the binding of  Benzamide derivatives with two different protein targets. In addition, authors have calculated other properties of these compounds.  However, my major concern is related to the stability of these compounds with the target, it is better for authors should use techniques such as molecular dynamics simulations to check the stability of compounds with top docking scores.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

This study does not have enough specifics and sequence. There are several comments to which need to give answers.

1. Reference 31 is not related to the description of the methods for calculating indexes of reactivity.

2. Reference 1 is unconvincing, irrelevant to reveal the meaning of the phrase under discussion.

3. Lines 74, 109: “basic” is a typo, it should be write “basis”.

4. What is the reason for the choice of a very limited double-zeta basis set of  6-31G*?

5. Reference 32 is not related to the method B3LYP/6-31G*

6. Reference 33 is not related to the description of the research methods ADME(T).

7. How is the Electrostatic Potential map directly related to reactionary ability? This statement is very controversial. It requires direct evidence of the correlation of the values of the electrostatic potential and the output of the product in a specific reaction. Otherwise, this is only an abstract statement.

8. In the section "2. Materials and Methods” lacks a details of the calculations in each of the subsections. In particular, the methodology of molecular docking, calculation of molecular properties, etc. is not at all described at all.

9. As I understand it, the 1a-1o compounds were not a newly synthesized as a part of this study. Thus, it is not recommended to write “new” in the title of the article and further in the text.

10. What is the basis for the choice of this particular library of compounds 1a-1o? There are no convincing arguments in the text of the article in favor of their choice.

11. 15 compounds is too small a selection of very similar compounds. For a qualitative study, number of compounds should be significantly increased.

12. What is the reason for choosing as the docking targets of the E. coli DNA gyrase and S. aureus DNA gyrase active sites? What are the prerequisites for this? This moment should be described in more reasonably.

13. In section 3.2.2. the analysis of various molecular properties of 1a-1o molecules is given. At the same time, line 180 indicates that these calculated parameters are necessary to understand the structure and functions of molecules. So where are the conclusions about their reactivity, etc.? For what purpose were all these molecular descriptors have been calculated?

14. Lines 257-259: “In the Designed Series of Compounds, The Highest Chemical Reactivity, Namely The Smallest Value of Homo - Lumo Gap Is Marked At Compound 1D (δe = 2.28 EV)” - what conclusion follows from this statement? It is necessary to cite specific evidence of the influence of Energy Gap on the reactivity, the reaction product yield, etc.

15. Figures 5b, 7b, 8b are compressed/stretched horizontally, they should be redrawn.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The authors have provided an explanation for my comment. I would recommend the manuscript can be accepted.

Author Response

We thank you for your comments!

Reviewer 3 Report

1. There is no answer to question #4.

2. Quoted from the authors' answer to question #7:

"As the charge distribution describes the interaction between molecules, the MEP can be used to determine the sites reactivity by emphasizing the electrophilic and nucleophilic attacks in the molecule."

It is clear that with the help of MESP it is possible to understand which of the centers of the molecule are electrophiles/nucleophiles. But, nevertheless, how can one build correlations between the theoretical data obtained as a result of the calculation of the Electrostatic Potential map and the experimental data on reactivity? A simple calculation of MESP without reference to the experimental yields of the reaction does not make sense.

Author Response

Please  see the attachment!

Author Response File: Author Response.pdf