Structure based virtual screening of novel inhibitors against multidrug resistant superbugs

Abstract

Pathogenic microorganisms are persistently expressing resistance towards present generation antibiotics and are on the verge of joining the superbug family. Recent studies revealed that, notorious pathogens such as Salmonella typhi, Shigella dysenteriae and Vibrio cholerae have acquired multiple drug resistance and the treatment became a serious concern. This necessitates an alternative therapeutic solution. Present study investigates the utility of computer aided method to study the mechanism of receptor-ligand interactions and thereby inhibition of virulence factors (shiga toxin of Shigella dysenteriae, cholera toxin of Vibrio cholerae and hemolysin-E of Salmonella typhi) by novel phytoligands. The rational designs of improved therapeutics require the crystal structure for the drug targets. The structures of the virulent toxins were identified as probable drug targets. However, out of the three virulent factors, the structure for hemolysin-E is not yet available in its native form. Thus, we tried to model the structure by homology modeling using Modeller 9v9. After extensive literature survey, we selected 50 phytoligands based on their medicinal significance and drug likenesses. The receptor-ligands interactions between selected leads and toxins were studied by molecular docking using Auto Dock 4.0. We have identified two novel sesquiterpenes, Cadinane [(1S, 4S, 4aS, 6S, 8aS)- 4- Isopropyl- 1, 6- dimethyldecahydronaphthalene] and Cedrol [(8α)-Cedran-8-ol] against Shiga (binding energy -5.56 kcal/mol) and cholera toxins (binding energy -5.33 kcal/mol) respectively which have good inhibitory properties. Similarly, a natural Xanthophyll, Violaxanthin [3S, 3'S, 5R, 5'R, 6S, 6'S)-5, 5', 6, 6'-Tetrahydro-5, 6:5', 6'-diepoxy-β, β-carotene-3, 3'-diol] was identified as novel therapeutic lead for hemolysin-E (binding energy of -5.99 kcal/mol). This data provide an insight for populating the pool of novel inhibitors against various drug targets of superbugs when all current generation drugs seem to have failed.

Keywords: Drug likenesses; Multiple drug resistance; Phytoligands; Sesquiterpenes; Shiga toxin; Superbugs.

Figure 1

Three dimensional structure of hemolysin-E of Salmonella typhi generated by homology modeling; (A) The secondary structure of the protein displayed in Chimera shown that the toxin has seven alpha helical domains; (B) The Ramachandran plot of the model indicate 98.2% residues (A, B, L in the plot) are most favored region and 1.8 % (a, b, l, p regions) residues are additional allowed regions revealed the stupendous quality of the model; (C) The overall quality factor of non-bonded interactions between different atoms types estimated by ERRAT is 92.17 implies good validity of our structure.

Figure 2

The docking simulations of novel phytoligands against probable drug targets of multidrug resistant pathogens. The ligands are displayed in the form of molecular surfaces and interacting residues and hydrogen bonds are shown in stick figures. (A) The interaction of shiga toxin (virulent factor of Shigella dysenteriae) and the best phytoligand, Cadinane is stabilized by weak interactions (residues Ile 24, Gly 25, Leu 39, Leu 38, Arg 21 Met 40 and Ile 41) with a minimum energy of -5.56 kcal/mol; (B) The docked conformation of Cholera toxin (virulent factor of Vibrio cholerae) and herbal ligand Cadinane is stabilized by a hydrogen bond with an energy minimum of -5.33 kcal/mol. The interacting residues are Lys 283, Val 285, Trp 318, Asp 624, Ser 623 and Tyr 609; (C) Hemolysin-E (virulent factor of Salmonella typhi) interacted with Violaxanthin by a hydrogen bond and other interactions (Lys 38, Asp41, Lys 45, Phe 71, Glu85, Gln 81 and His 292) by the free energy minimum of –5.99 kcal/mol. Present docking studies revealed that herbal leads have good binding affinities against the drug targets and the data has crucial applications in further studies.