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Pharmacophore generation, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on benzamide analogues as FtsZ inhibitors.
J Biomol Struct Dyn. 2018 Sep; 36(12):3218-3230.JB

Abstract

FtsZ is an appealing target for the design of antimicrobial agent that can be used to defeat the multidrug-resistant bacterial pathogens. Pharmacophore modelling, molecular docking and molecular dynamics (MD) simulation studies were performed on a series of three-substituted benzamide derivatives. In the present study a five-featured pharmacophore model with one hydrogen bond acceptors, one hydrogen bond donors, one hydrophobic and two aromatic rings was developed using 97 molecules having MIC values ranging from .07 to 957 μM. A statistically significant 3D-QSAR model was obtained using this pharmacophore hypothesis with a good correlation coefficient (R2 = .8319), cross validated coefficient (Q2 = .6213) and a high Fisher ratio (F = 103.9) with three component PLS factor. A good correlation between experimental and predicted activity of the training (R2 = .83) and test set (R2 = .67) molecules were displayed by ADHRR.1682 model. The generated model was further validated by enrichment studies using the decoy test and MAE-based criteria to measure the efficiency of the model. The docking studies of all selected inhibitors in the active site of FtsZ protein showed crucial hydrogen bond interactions with Val 207, Asn 263, Leu 209, Gly 205 and Asn-299 residues. The binding free energies of these inhibitors were calculated by the molecular mechanics/generalized born surface area VSGB 2.0 method. Finally, a 15 ns MD simulation was done to confirm the stability of the 4DXD-ligand complex. On a wider scope, the prospect of present work provides insight in designing molecules with better selective FtsZ inhibitory potential.

Authors+Show Affiliations

a Department of Pharmaceutical Sciences , Utkal University, Vani Vihar , Bhubaneswar 751004 , Odisha , India .b Department of Pharmaceutical Chemistry , J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore) , Ooty 643001 , Tamil Nadu , India.b Department of Pharmaceutical Chemistry , J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore) , Ooty 643001 , Tamil Nadu , India.a Department of Pharmaceutical Sciences , Utkal University, Vani Vihar , Bhubaneswar 751004 , Odisha , India .

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28938860

Citation

Tripathy, Swayansiddha, et al. "Pharmacophore Generation, Atom-based 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation Studies On Benzamide Analogues as FtsZ Inhibitors." Journal of Biomolecular Structure & Dynamics, vol. 36, no. 12, 2018, pp. 3218-3230.
Tripathy S, Azam MA, Jupudi S, et al. Pharmacophore generation, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on benzamide analogues as FtsZ inhibitors. J Biomol Struct Dyn. 2018;36(12):3218-3230.
Tripathy, S., Azam, M. A., Jupudi, S., & Sahu, S. K. (2018). Pharmacophore generation, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on benzamide analogues as FtsZ inhibitors. Journal of Biomolecular Structure & Dynamics, 36(12), 3218-3230. https://doi.org/10.1080/07391102.2017.1384401
Tripathy S, et al. Pharmacophore Generation, Atom-based 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation Studies On Benzamide Analogues as FtsZ Inhibitors. J Biomol Struct Dyn. 2018;36(12):3218-3230. PubMed PMID: 28938860.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacophore generation, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on benzamide analogues as FtsZ inhibitors. AU - Tripathy,Swayansiddha, AU - Azam,Mohammed Afzal, AU - Jupudi,Srikanth, AU - Sahu,Susanta Kumar, Y1 - 2017/10/11/ PY - 2017/9/25/pubmed PY - 2019/5/29/medline PY - 2017/9/24/entrez KW - 3D-QSAR KW - 3D-QSAR = three-dimensional quantitative structure–activity relationship KW - AAE = average absolute error KW - AE = average error KW - FtsZ = filamentous temperature sensitive protein Z KW - GTPase KW - Glide XP = glide extra precision KW - MAE = mean absolute error KW - MD = molecular dynamics KW - MIC = minimum inhibitory concentration KW - MM-GBSA = molecular mechanics-generalized born surface area KW - MPE = mean positive error KW - NNE = number of negative errors KW - NPE = number of positive errors KW - PLS = partial least square KW - Q2 = correlation coefficient for test set KW - R2 = correlation coefficient KW - RMSD = root-mean-square deviation KW - RMSE = root-mean-square error KW - SD = standard deviation KW - dynamics simulation KW - molecular docking KW - pharmacophore hypotheses KW - σAE = standard deviation of the absolute error SP - 3218 EP - 3230 JF - Journal of biomolecular structure & dynamics JO - J Biomol Struct Dyn VL - 36 IS - 12 N2 - FtsZ is an appealing target for the design of antimicrobial agent that can be used to defeat the multidrug-resistant bacterial pathogens. Pharmacophore modelling, molecular docking and molecular dynamics (MD) simulation studies were performed on a series of three-substituted benzamide derivatives. In the present study a five-featured pharmacophore model with one hydrogen bond acceptors, one hydrogen bond donors, one hydrophobic and two aromatic rings was developed using 97 molecules having MIC values ranging from .07 to 957 μM. A statistically significant 3D-QSAR model was obtained using this pharmacophore hypothesis with a good correlation coefficient (R2 = .8319), cross validated coefficient (Q2 = .6213) and a high Fisher ratio (F = 103.9) with three component PLS factor. A good correlation between experimental and predicted activity of the training (R2 = .83) and test set (R2 = .67) molecules were displayed by ADHRR.1682 model. The generated model was further validated by enrichment studies using the decoy test and MAE-based criteria to measure the efficiency of the model. The docking studies of all selected inhibitors in the active site of FtsZ protein showed crucial hydrogen bond interactions with Val 207, Asn 263, Leu 209, Gly 205 and Asn-299 residues. The binding free energies of these inhibitors were calculated by the molecular mechanics/generalized born surface area VSGB 2.0 method. Finally, a 15 ns MD simulation was done to confirm the stability of the 4DXD-ligand complex. On a wider scope, the prospect of present work provides insight in designing molecules with better selective FtsZ inhibitory potential. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/28938860/Pharmacophore_generation_atom_based_3D_QSAR_molecular_docking_and_molecular_dynamics_simulation_studies_on_benzamide_analogues_as_FtsZ_inhibitors_ DB - PRIME DP - Unbound Medicine ER -