Aldose reductase inhibitors for diabetic complications: Receptor induced atom-based 3D-QSAR analysis, synthesis and biological evaluation.
Herein, atom-based 3D-QSAR analysis was performed using receptor-guided alignment of 46 flavonoid inhibitors of aldose reductase (ALR2) enzyme. 3D-QSAR models were generated in PHASE programme, and the best model corresponding to PLS factor four (QSAR4), was selected based on different statistical parameters (i.e., Rtrain(2), 0.96; Qtest(2) 0.81; SD, 0.26). The contour plots of different structural properties generated from the selected model were utilized for the designing of five new congener molecules. These designed molecules were duly synthesized, and evaluated for their in vitro ALR2 inhibitory activity that resulted in the micromolar (IC50<22μM) activity of all molecules. Thus, the newly designed molecules having ALR inhibitory potential could be employed for the management of diabetic complications.
Department of Chemistry, Punjabi University, Patiala 147002, Punjab, India.
Bhawna
B
Vyas
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, Punjab, India.
Manjinder
M
Singh
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, Punjab, India.
Maninder
M
Kaur
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, Punjab, India.
Malkeet Singh
MS
Bahia
Division of Pharmacology, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, Punjab, India.
Amteshwar Singh
AS
Jaggi
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, Punjab, India.
Om
O
Silakari
Department of Chemistry, Punjabi University, Patiala 147002, Punjab, India. Electronic address: bhawnaom@rediffmail.com.
Baldev
B
Singh
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D048909:Diabetes Complications / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D004791:Enzyme Inhibitors; D005419:Flavonoids; D000449:Aldehyde Reductase
Aldose reductase (ALR2); Atom-based 3D-QSAR; Diabetic complications; Docking analysis; Flavonoid derivatives