In silico evaluation of isatin-based derivatives with RNA-dependent RNA polymerase of the novel coronavirus SARS-CoV-2.

Isatin (1H-indole-2,3-dione)-containing compounds have been shown to possess several remarkable biological activities. We had previously explored a few isatin-based imidazole derivatives for their predicted dual activity against both inflammation and cancer. We explored 47 different isatin-based derivatives (IBDs) for other potential biological activities using in silico tools and found them to possess anti-viral activity. Using AutoDock tools, the binding site, binding energy, inhibitory constant/Ki and receptor-ligand interactions for each of the compounds were analyzed against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The partition coefficient (logP) values were predicted using MedChem Designer tool. Based on the best Ki, binding energy and the ideal range of logP (between 1.0 and 3.0), 10 out of total 47 compounds were deemed to be prospective RdRp inhibitors. Some of these compounds gave better Ki, binding energy and logP values when compared to standard RdRp inhibitors, such as remdesivir (REM) (Ki = 15.61 µM, logP = 2.2; binding energy = -6.95), a clinically approved RdRp inhibitor and nine other RdRp inhibitors. The results showed that the 10 selected IBDs could be further explored. Molecular dynamics simulations (MDSs) showed that the selected RdRp-IBD complexes were highly stable compared to the native RdRp and RdRp-REM complex during 100 ns time periods. DFT studies were performed for the compounds 16a, 24a, 28a, 38a and 40a, to evaluate the charge transfer mechanism for the interactions between the IBDs and the RdRp residues. Among these, ADME profiling revealed that 28a is a possible lead compound which can be explored further for anti-RdRp activity in vitro. Communicated by Ramaswamy H. Sarma.

Analysing the antidepressant and drug efflux competence of Clitoria ternateaL. as P-glycoprotein inhibitor to facilitate blood brain barrier

Clitoria ternateaL. is a vital ayurvedic herbfeatured with a wide spectrum of mental health benefits. The present study investigates the competence of the plant against depression and to inhibit the membrane efflux protein P-glycoprotein (P-gp) that can regulate and restrict drug permeation into the brain. Antidepressant competence of the aqueous plant extract was assessed by animal despair studies on depression induced female mice models. The P-glycoprotein inhibitory potential of active phytocompounds was evaluated by molecular docking assay and substantiated by a cell line study. The in vivostudies exhibited a significant difference in the immobility time thereby establishing antidepressant activity. The histopathological sections from cortex region of treated brain showed decreased degenerative changes. Ten imperative phytocompounds facilitated docking complexes against P-glycoprotein among which Kaempferol 3-O-(2״,6״-di-O-rhamnopyranosyl) glucopyranoside exhibited a finest docking score of -12.569 kcal mol-1. Conversely it was attested by the rhodamine transport assay that demonstrated the inhibitory potential to surpass blood brain barrier. The outcome of the study endorses the efficacy of Clitoria ternateaL. as an idyllic brain drug and facilitates brain permeability.