Identification of novel antifungal lead compounds through pharmacophore modeling, virtual screening, molecular docking, antimicrobial evaluation, and gastrointestinal permeation studies

Singh, Aarti; Paliwal, Sarvesh; Sharma, Manu; Mittal, Anupama; Sharma, Swapnil; Tripathi, Neetika; Tilak, Amita

doi:10.1080/07391102.2016.1218369

Cited by 6 publications

(3 citation statements)

References 14 publications

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“…During the modeling it was observed that compounds 9 showed ahigh error ratio, eventually it was removed from the dataset with an aim to further enhance the quality of the model. This kind of behavior of compound 9 indicates typographical error or inappropriate experiment observation or may be different mechanism of action 12 . Many pharmacophore models were generated and statistically evaluated.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators

Tripathi

Paliwal

Sharma

et al. 2018

Sci Rep

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In view of the role of sEH (soluble epoxide hydrolase) in hypertension, we have developed a rigorously validated pharmacophore model containing one HBA (Hydrogen Bond Acceptor), two HY (Hydrophobic) and one RA (Ring Aromatic) features. The model was used as a query to search the NCI (National Cancer Institute) and Maybridge database leading to retrieval of many compounds which were sorted on the basis of predicted activity, fit value and Lipinski’s violation. The selected compounds were docked into the active site of enzyme soluble epoxide hydrolase. Potential interactions were observed between the features of the identified hits and the amino acids present in the docking site. The three selected compounds were subjected to in vitro evaluation using enzyme- based assay and the isolated rat aortic model followed by cytotoxicity studies. The results demonstrate that the identified compounds are potent, safe and novel soluble epoxide hydrolase inhibitors.

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Section: Resultsmentioning

confidence: 99%

Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators

Tripathi

Paliwal

Sharma

et al. 2018

Sci Rep

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“…Using the same chemical features and parameters that were used for model development, 99 spreadsheets were generated at a 99% confidence level . Statistical data of the selected pharmacophore model was better than randomly generated models, which means that the selected pharmacophore is not generated by chance correlation (Figure ).…”

Section: Pharmacophore Model Validationmentioning

confidence: 99%

Identification of Novel Rho-Kinase-II Inhibitors with Vasodilatory Activity

Kesar

Paliwal

Mishra

et al. 2020

ACS Med. Chem. Lett.

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Small GTPase protein Rho-kinase (ROCK) plays an important role in the pathogenesis of hypertension. Inhibition of ROCK II brings about the biochemical changes leading to vascular smooth muscles relaxation, finally resulting into potent antihypertensive activity. In the quest for potent ROCK-II inhibitors, a ligand-based pharmacophore containing four essential chemical features, namely two hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), and one hydrophobe (HY), was developed and rigorously validated. The pharmacophore was used for virtual screening, and hits retrieved from the National Cancer Institute (NCI) database were sorted on the basis of fit value, estimate value, and Lipinski's violation. Potential feature interaction of hits was also observed during docking studies with the amino acids present in the active site of Rho-kinase. Based on the above screening, three hits (NSC 2488, NSC 2888, and NSC 4231) were chosen and subjected to in vitro Rho-kinase enzyme-based assay, followed by ex vivo rat aortic vasodilatory assay. All three compounds showed good biological activity as predicted by the model and confirmed by the docking studies.

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“…Pharmacophore model was generated with an endeavor to represent the collection of key features that are vital for biological activity [ 13 ]. The HypoGen method was used for modeling pharmacophores [ 14 ]. This method utilizes the biological activities of the shortlisted chemical compounds to produce the system using DS V2.0 software.…”

Section: Methodsmentioning

confidence: 99%

Pharmacophore-driven identification of N-methyl-D-receptor antagonists as potent neuroprotective agents validated using in vivo studies

Sharma

Mittal

Singh

et al. 2020

Biology Methods and Protocols

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Alzheimer’s disease, apparently the most widespread reason behind dementia, is delineated by a continuous cognitive weakening in the aged. During its progression, N-Methyl-D-Aspartate receptor antagonists are known to play a pivotal part in the mechanisms of learning and memory. Since there is an unmet medical need for the treatment of Alzheimer’s disease, we aim to identify possible chemical compounds targeted towards N-Methyl-D-Aspartate receptors. Three-dimensional models are developed to unveil some of the essential characteristics of the N-Methyl-D-Aspartate receptors by using a collection of already discovered N-Methyl-D-Aspartate receptor inhibitors. This is followed by virtual screening, which results in novel chemical compounds having the potential to inhibit N-Methyl-D-Aspartate receptors. Molecular docking studies and analysis promulgated two lead compounds with a high Libdock score. The compounds are shortlisted based on high estimated activity, fit values, LibDock score, no violation of Lipinski’s and availability for procuring. Finally, the shortlisted compounds are tested by employing in-vivo studies, which we further propose as potential NMDA inhibitors for treating Alzheimer’s Disease.

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Identification of novel antifungal lead compounds through pharmacophore modeling, virtual screening, molecular docking, antimicrobial evaluation, and gastrointestinal permeation studies

Cited by 6 publications

References 14 publications

Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators

Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators

Identification of Novel Rho-Kinase-II Inhibitors with Vasodilatory Activity

Pharmacophore-driven identification of N-methyl-D-receptor antagonists as potent neuroprotective agents validated using in vivo studies

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