Molecular Docking Analysis of Clostridium Perfringens Beta Toxin Model with Potential Inhibitors from the ZINC Database

Overview

Journal Bioinformation

Specialty Biology

Date 2022 Feb 17

PMID 35173385

Authors

Amit Kumar Solanki

Abhishek Acharya

Himani Kaushik

Bharti Bhatia

Lalit C Garg

Affiliations

Soon will be listed here.

Abstract

Beta toxin from Clostridium perfringens after being secreted in gut is capable of causing necrotic enteritis in humans and several other animal species and does not respond to routinely used antibiotics. Therefore, there is a need to design an effective inhibitor for the Clostridium perfringens beta toxin (CPB) using cutting edge drug discovery technologies. Hence, potential CPB inhibitors were identified using computer aided screening of compounds from the ZINC database. Further, we document the molecular docking analysis of Clostridium perfringens beta toxin model (that revealed 4 binding pockets, A-D) with the identified potential inhibitors. We show that ZINC291192 [N-[(1-methylindol-3-yl) methyl eneamino]-7,10-dioxabicyclo[4.4.0]deca-2,4,11-triene-8- carboxamide] has optimal binding features with calculated binding energy of -10.38 kcal/mol and inhibition constant of 24.76 nM for further consideration.

References

Kelley L, Mezulis S, Yates C, Wass M, Sternberg M . The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015; 10(6):845-58. PMC: 5298202. DOI: 10.1038/nprot.2015.053. View

Yu J, Zhou Y, Tanaka I, Yao M . Roll: a new algorithm for the detection of protein pockets and cavities with a rolling probe sphere. Bioinformatics. 2009; 26(1):46-52. DOI: 10.1093/bioinformatics/btp599. View

HUNTER S, Brown J, Oyston P, Sakurai J, Titball R . Molecular genetic analysis of beta-toxin of Clostridium perfringens reveals sequence homology with alpha-toxin, gamma-toxin, and leukocidin of Staphylococcus aureus. Infect Immun. 1993; 61(9):3958-65. PMC: 281100. DOI: 10.1128/iai.61.9.3958-3965.1993. View

ALOUF J . Pore-forming bacterial protein toxins: an overview. Curr Top Microbiol Immunol. 2001; 257:1-14. View

Steinthorsdottir V, Halldorsson H, Andresson O . Clostridium perfringens beta-toxin forms multimeric transmembrane pores in human endothelial cells. Microb Pathog. 2000; 28(1):45-50. DOI: 10.1006/mpat.1999.0323. View

Kawabata T . Detection of multiscale pockets on protein surfaces using mathematical morphology. Proteins. 2009; 78(5):1195-211. DOI: 10.1002/prot.22639. View

Luginbuhl A . [The necrotizing enteritis by Clostridium perfringens type C in piglets: practical observations, control and epidemiology]. Schweiz Arch Tierheilkd. 2002; 144(6):263-73. DOI: 10.1024/0036-7281.144.6.263. View

Fisher D, Fernandez-Miyakawa M, Sayeed S, Poon R, Adams V, Rood J . Dissecting the contributions of Clostridium perfringens type C toxins to lethality in the mouse intravenous injection model. Infect Immun. 2006; 74(9):5200-10. PMC: 1594841. DOI: 10.1128/IAI.00534-06. View

Laskowski R, Rullmannn J, MacArthur M, Kaptein R, Thornton J . AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR. 1996; 8(4):477-86. DOI: 10.1007/BF00228148. View

10.

Kozlikova B, Sebestova E, Sustr V, Brezovsky J, Strnad O, Daniel L . CAVER Analyst 1.0: graphic tool for interactive visualization and analysis of tunnels and channels in protein structures. Bioinformatics. 2014; 30(18):2684-5. DOI: 10.1093/bioinformatics/btu364. View

11.

Altschul S, Madden T, Schaffer A, Zhang J, Zhang Z, Miller W . Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997; 25(17):3389-402. PMC: 146917. DOI: 10.1093/nar/25.17.3389. View

12.

Benkert P, Biasini M, Schwede T . Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics. 2010; 27(3):343-50. PMC: 3031035. DOI: 10.1093/bioinformatics/btq662. View

13.

Nagahama M, Hayashi S, Morimitsu S, Sakurai J . Biological activities and pore formation of Clostridium perfringens beta toxin in HL 60 cells. J Biol Chem. 2003; 278(38):36934-41. DOI: 10.1074/jbc.M306562200. View

14.

Schraw W, Li Y, McClain M, van der Goot F, Cover T . Association of Helicobacter pylori vacuolating toxin (VacA) with lipid rafts. J Biol Chem. 2002; 277(37):34642-50. DOI: 10.1074/jbc.M203466200. View

15.

Sayeed S, Uzal F, Fisher D, Saputo J, Vidal J, Chen Y . Beta toxin is essential for the intestinal virulence of Clostridium perfringens type C disease isolate CN3685 in a rabbit ileal loop model. Mol Microbiol. 2007; 67(1):15-30. DOI: 10.1111/j.1365-2958.2007.06007.x. View

16.

Irwin J . Using ZINC to acquire a virtual screening library. Curr Protoc Bioinformatics. 2008; Chapter 14:14.6.1-14.6.23. DOI: 10.1002/0471250953.bi1406s22. View

17.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

18.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

19.

Guex N, Peitsch M . SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis. 1998; 18(15):2714-23. DOI: 10.1002/elps.1150181505. View

20.

Bhattacharya D, Cheng J . 3Drefine: consistent protein structure refinement by optimizing hydrogen bonding network and atomic-level energy minimization. Proteins. 2012; 81(1):119-31. PMC: 3634918. DOI: 10.1002/prot.24167. View