docking

Alpha amylase is one of the important targets in the treatment of diabetes mellitus that work by preventing the digestion of carbohydrates. Many alpha amylase inhibitors with diverse chemical structures and modes of protein interaction have been designed on the basis of their ability to compete with alpha amylase enzyme. This study involves the molecular docking of certain novel isoxazole incorporated coumarin derivatives as potent alpha amylase inhibitory agents. The compounds were computationally designed and optimized with the docking to investigate the interactions between the target compounds and the amino acid residues of theα-amylase enzyme. The inhibitory activities against human alpha amylase enzyme were investigated by molecular docking using the autodock software. All the designed compounds were showed good binding energy when compared with the binging energies of standard drugs such as acarbose (for anti-diabetic activity). Among all the designed compounds, compoundI1 and I3 have more binding energy values when compared with standard drugs. Here we also studied the molecular properties of designed compound using molinspiration software. Further we planned to synthesis these isoxazole derivatives and screen for in vitroanti diabetic activity.

Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis and accumulating evidence suggests that overexpression of FASN is common in many cancers. To date, not many compounds are known to inhibit FASN. Thus, our aim was to explore more lead compounds which are able to inhibit FASN. High affinity compounds for FASN were searched among a database of chemical structures comprising 9,127 approved drugs, chemical isolates from traditional medicinal herbs, and regulated chemicals, termed the SWEETLEAD. The screening protocol consisted of a high-throughput pharmacophore screening followed by an extensive docking and scoring study. Three different pharmacophore models and a merged pharmacophore model were generated using three different inactive crystal structures of FASN. Pharmacophore-based screening yielded overall 1,661 hits. Afterwards, all these hit compounds were docked to the inactive form of FASN using docking and scoring protocols. The best pose was further evaluated based on the existence of key residues for antagonist binding in its vicinity which retrieved 38 hits. After final evaluations based on S-score, 12 hits were revealed. Although the experimental validation of these compounds are lacking, computational methods predicts them as strong binders. Further experimental validation of these compounds will confirm this in silico study and their potential role of these hits in treatment of cancer with high FASN expression. 

Triazine derivatives were reported to show a wide range of biological activities. Hence, it was planned to perform docking studies, synthesize and screen these designed compounds for their in vivo anti-inflammatory activity. In order to study the interaction of ligands with the binding site of the enzyme, the triazine derivatives were docked on cyclooxygenase-2 (COX-2) enzyme using the drug design software Maestro 9.5, Schrodinger, USA. The series of 8 compounds showing good Glide score (G-score) was synthesized to form 4-anilinoquinoline triazines. The structures of the compounds were confirmed by IR, 1H NMR and mass spectroscopy and the compounds were screened for anti-inflammatory activity by carrageenan- induced rat hind paw edema method, using Diclofenac as the standard. The G-scores of all the 8 compounds were closer to the scores displayed by the standard drugs, celecoxib and SC-558, there by suggesting that all the compounds interacted very well with the COX-2 enzyme. The in vivo anti-inflammatory activity results revealed that all the compounds displayed % inhibition of edema more than 90, which was better than that shown by the standard drug, Diclofenac. Amongst all the compounds, 3b demonstrated the highest G-score as well as the highest anti-inflammatory activity. Hence, this compound may be explored as a potential lead molecule for further development.

Gymnema sylvestre has been extensively evaluated for its in vitro and in vivo activity against diabetes mellitus. The leaves of the shrub Gymnema sylvestre contain a complex of pentacyclic triterpenes known as gymnemic acids that have been reported as potential therapeutic agents in the treatment of diabetes. The present study reveals the relationship between the structure and function of the medicinally important constituents of this plant. To understand the binding mechanisms of these active constituents, molecular modelling studies has been performed with dipeptidyl peptidase-4, protein tyrosine phosphatase 1B, sodium potassium ATPase, aldose reductase and glycogen synthase kinase-3β as target proteins using XP docking program of Glide, version 9.2, Schrödinger suit. These constituents showed favourable interactions with the amino acid residues at the active site, their by substantiating their proven efficacy as antidiabetic agents. The present study also gives an insight to the probable herb-drug interaction and reason for sudden hypoglycemic shocks that may occur on concurrent administration of Gymnema extract and synthetic drug, Glimepiride, for the treatment of diabetes.