The α‐amylase inhibition has been considered as an effective therapeutic approach against chronic Type 2 Diabetes mellitus (DM). In the present study, a series of biphenylcarbonitrile‐thiazolidinedione conjugates have been synthesized and evaluated for their antidiabetic activity viaα‐amylase inhibition. It was found that most of the conjugates (14 a–j) exhibited significant α‐amylase inhibition activity compared to the standard drug Acarbose. Off these, compound 14 b,14 c and 14 dwere most potent with IC50 value 0.13 μM, 0.15 μM and0.13 μM respectively. To ascertain ligand‐receptor interactions, the in silico molecular docking studies of these conjugates (14 a–j) have been carried out into the Acarbose active site of barley (malt) α‐amylase enzyme. The results have shown fair corroboration between significant α‐amylase inhibition activity of 14 b, 14 c and 14 d and their docking scores compared to the standard drug Acarbose. This study demonstrated that biphenylcarbonitrile‐thiazolidinedione conjugate could be a plausible pharmacophore for targeting α‐amylase for the treatment of Type 2 Diabetes mellitus.

Diabetes is a major health issue that half a billion people affected worldwide. It is a serious, long-term medical condition majorly impacting the lives and well-being of individuals, families, and societies at large. It is amongst the top 10 diseases responsible for the death amongst adults with an expected rise to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. The carbohydrates absorbed into the body are hydrolyzed by pancreatic α-amylase and other enzymes, human α-glucosidase. The α-amylase and α-glucosidase are validated therapeutic targets in the treatment of Type II diabetes (T2DM) as they play a vital role in modulating the blood glucose post meal. Herein, we report novel and diverse molecules as potential candidates, with predicted affinity for α-amylase and α-glucosidase. These molecules have been identified via hierarchical multistep docking of small molecules database with the estimated binding free energies. A Glide XP Score cutoff −8.00 kcal/mol was implemented to filter out non potential molecules. Four molecules viz. amb22034702, amb18105639, amb17153304, and amb9760832 have been identified after an exhaustive computational study involving, evaluation of binding interactions and assessment of the pharmacokinetics and toxicity profiles. The in-depth analysis of protein– ligand interactions was performed using a 100ns molecular dynamics (MD) simulation to establish the dynamic stability. Furthermore MM-GBSA based binding free energies were computed for 1000 trajectory snapshots to ascertain the strong binding affinity of these molecules for α-amylase and αglucosidase. The identified molecules can be considered as promising candidates for further drug development through necessary experimental assessments.

This study deals with the quantitative structureactivity relationship (QSAR) study of a series of 5-alkylidenepyridazine-3 (2H)-one as a novel non cAMP-based antiplatelet agent, using molecular descriptor derived from the 3D representation of the model with the CS Chem office version 8.0. Several types of molecular descriptor such as electronic, thermodynamic and steric have been used to derive a QSAR model between platelet inhibitory activity and structural properties. The best model for the prediction of platelet inhibitory activity was obtained by applying sequential multiple linear regression analysis method. Statically significant model with r 2 [ 0.87 was obtained by using ovality (OV), dipole moment on z-axis (DPL 3 ), HOMO energy (HE), standard Gibbs free energy (SGFE), total energy (TOE), torsion energy (TE) and non-1,4 VDW energy (NVDWE) descriptors. Regression coefficient of all descriptors used is significant at more than 99% level. Result shows that dipole moment DPL 3 and OV are the principle descriptors for the inhibition of platelet aggregations. The model was also tested successfully for internal q 2 [ 0.738 and external predictive r 2 [ 0.520 validation criteria. We demonstrate that the steric, topological and electronic descriptors play an important role in inhibition of platelet aggregation of the alkylidenepyridazin-3-ones.

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