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Journal of Molecular Modeling

, 25:360 | Cite as

Computer-aided identification of lead compounds as Staphylococcal epidermidis FtsZ inhibitors using molecular docking, virtual screening, DFT analysis, and molecular dynamic simulation

  • Swayansiddha TripathyEmail author
  • Susanta Kumar Sahu
  • Mohammed Afzal Azam
  • Srikanth Jupudi
Original Paper
First Online:
  • 41 Downloads

Abstract

In an effort to face the multiple drug-resistant bacteria, various approaches have been discovered to design potent compounds and search new targets through computational design tools. With an aim to identify selective inhibitors against filamentous temperature-sensitive mutant Z (FtsZ), a library of Phase database compounds have been virtually screened. High-throughput virtual screening of compounds against Staphylococcal epidermidis FtsZ protein (4M8I) was performed using three sequential docking modes like high-throughput virtual screening, Glide standard precision, followed by Glide extra precision. Four top-ranked compounds were selected from molecular mechanics-generalized Born surface area (MM-GBSA) binding energy with better predicted free binding energies of − 89.309, − 54.382, − 53.667, and − 52.133 kcal/mol, respectively. It is also showed that the contribution of van der Waals and electrostatic solvation energy terms are playing a major part to make the hit molecule (T6288784) binding to S. epidermidis FtsZ protein. The result of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and energy gap analysis predicts the molecular reactivity and stability of hit molecules. Subsequently, Lipinski’s rule of five and properties of absorption, distribution, metabolism, and excretion (ADME) were to calculate their bioavailability. The average binding energy − 9.67 kcal/mol of the best proposed hit molecule (T6288784) was found with half-maximal inhibitory concentration (IC50) value to be 75.53 nM. A 15-ns molecular dynamics simulation study revealed the stable conformation of hit molecule. On a wide-range research discipline, in silico studies of our proposed compound confirm promising results and can be successfully used towards the development of novel FtsZ inhibitor with better binding affinity.

Graphical Abstract

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Keywords

FtsZ  Molecular docking  DFT calculation  ADME analysis  Molecular dynamics simulation 

Abbreviations

FtsZ

filamentous temperature-sensitive protein Z

GTP

guanosine 5′-triphosphate

GDP

guanosine 5′-diphosphate (GTP)

Glide SP

Glide standard precision

Glide XP

Glide extra precision

eV

electron volt

MM-GBSA

molecular mechanics-generalized Born surface area

MD

molecular dynamics

ADME

absorption, distribution, metabolism, excretion

IC50

half-maximal inhibitory concentration

dHB

estimated number of hydrogen bonds that would be donated by the solute to water molecules in an aqueous solution

aHB

estimated number of hydrogen bonds that would be accepted by the solute from water molecules in an aqueous solution

QPlogPw

predicted water/gas partition coefficient

QPlogPoct

predicted octanol/gas partition coefficient

QPlogPo/W

predicted octanol/water partition coefficient

QPlogS

predicted aqueous solubility, logarithm S S in mol dm−3

QPlogHERG

predicted IC50 value for blockage of HERG K+ channels

QPPCaco

predicted apparent Caco-2 cell permeability in nm/sec

QPlogBB

predicted brain/blood partition coefficient

QPPMDCK

predicted apparent Madin-Darby canine kidney cell permeability in nm/sec

QPlogKp

predicted skin permeability

QPlogKhsa

prediction of binding to human serum albumin

PHOA

percent human oral absorption

nM

nano molar

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Notes

Acknowledgments

The authors would like to thank the Head of the Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ooty, India, and the Innovative Informatica Technologies, Hyderabad, India, for supporting the use of the software Schrödinger.

Funding information

We would like to thank the Department of Science and Technology (DST), the Women Scientist Scheme-A (WOS-A), and the Ministry of Science and Technology, Government of India, for the support (File No. SR/WOSA/CS-1108/2015- G).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

894_2019_4238_MOESM1_ESM.docx (1.7 mb)
ESM 1 (DOCX 1722 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.University Department of Pharmaceutical SciencesUtkal UniversityBhubaneswarIndia
  2. 2.Department of Pharmaceutical ChemistryJ.S.S. College of PharmacyUdhagamandalamIndia

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