Integrated pharmacophore and docking-based designing of dual inhibitors of aldose reductase (ALR2) and protein tyrosine phosphatase 1B (PTP1B) as novel therapeutics for insulin-resistant diabetes and its complications

• Published in: Journal of chemometrics 2015-02, Vol.29 (2), p.109-125
• Main Authors: Vyas, Bhawna, Silakari, Om, Kaur, Maninder, Singh, Baldev
• Format: Article
• Language: English
• Subjects: aldose reductase (ALR2); Binding; Diabetes; diabetic complications; docking; Enzymes; hierarchical virtual screening; Inhibition; Inhibitors; pharmacophore; Proteins; PTP1B; Reductases; Searching; Standard deviation; Three dimensional; Tyrosine
• ISSN: 0886-9383; 1099-128X
• DOI: 10.1002/cem.2682

The dual inhibitors against aldose reductase (ALR2) and protein tyrosine phosphatase 1B (PTP1B) may present an anti‐diabetic potency in insulin resistance without risks of serious diabetic complications. Therefore, in the present study, we constructed two separate pharmacophore mapping‐based 3D quantitative structure–activity relationship models for ALR2 (AADRR.11093 with standard deviation 0.663, Rtrain2 0.719, F 22.3, root‐mean‐square error 0.705, Qtest2 0.647, Pearson‐r 0.802) and PTP1B (AARR.155 with standard deviation 0.146, Rtrain2 0.945, F 82.70, root‐mean‐square error 0.351, Qtest2 0.621, Pearson‐r 0.831) employing the dataset of 54 flavonoids as ALR2 inhibitors and 46 naphthoquinones as PTP1B inhibitors to identify structural features necessary for the inhibition of both enzymes. These models were subsequently used as 3D query search for hierarchical virtual screening‐based designing using the PHASE database of 1.5 million compounds. Designed dual inhibitors were further subjected to GLIDE XP docking analysis using high‐resolution 3D structures of ALR2 (1US0, at resolution of 0.66 Å) and PTP1B (2F71 at resolution of 1.55 Å) available in the Protein Data Bank to authenticate identified structural features with important binding interactions necessary for dual inhibition. Copyright © 2014 John Wiley & Sons, Ltd. The dual inhibitors against against Q2 aldose reductase (ALR2) and protein tyrosine phosphatase 1B (PTP1B) may present an anti‐diabetic potency in insulin resistance and its diabetic complications. In the present study, we constructed two separate pharmacophore models for ALR2 and PTP1B that were subsequently used as 3D query search for hierarchical virtual screening‐based designing. Designed dual inhibitors were further subjected to docking analysis using high‐resolution 3D structures of ALR2(1US0) and PTP1B (2F71) to authenticate identified structural features with important binding interactions necessary for dual inhibition.