Deciphering the Potential of Pre and Pro-Vitamin D of Mushrooms against Mpro and PLpro Proteases of COVID-19: An In Silico Approach.

Vitamin D's role in combating the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, has been established in unveiling viable inhibitors of COVID-19. The current study investigated the role of pre and pro-vitamin D bioactives from edible mushrooms against Mpro and PLpro proteases of SARS-CoV-2 by computational experiments. The bioactives of mushrooms, specifically ergosterol (provitamin D2), 7-dehydrocholesterol (provitamin-D3), 22,23-dihydroergocalciferol (provitamin-D4), cholecalciferol (vitamin-D3), and ergocalciferol (vitamin D2) were screened against Mpro and PLpro. Molecular docking analyses of the generated bioactive protease complexes unravelled the differential docking energies, which ranged from -7.5 kcal/mol to -4.5 kcal/mol. Ergosterol exhibited the lowest binding energy (-7.5 kcal/mol) against Mpro and PLpro (-5.9 kcal/mol). The Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and MD simulation analyses indicated that the generated complexes were stable, thus affirming the putative binding of the bioactives to viral proteases. Considering the pivotal role of vitamin D bioactives, their direct interactions against SARS-CoV-2 proteases highlight the promising role of bioactives present in mushrooms as potent nutraceuticals against COVID-19.

Neuroprotective effects of combined trimetazidine and progesterone on cerebral reperfusion injury.

Cerebral ischemia-reperfusion injury induces multi-dimensional damage to neuronal cells through exacerbation of critical protective mechanisms. Targeting more than one mechanism simultaneously namely, inflammatory responses and metabolic energy homeostasis could provide additional benefits to restrict or manage cerebral injury. Being proven neuroprotective agents both, progesterone (PG) and trimetazidine (TMZ) has the potential to add on the individual therapeutic outcomes. We hypothesized the simultaneous administration of PG and TMZ could complement each other to synergize, or at least enhance neuroprotection in reperfusion injury. We investigated the combination of PG and TMZ on middle cerebral artery occlusion (MCAO) induced cerebral reperfusion injury in rats. Molecular docking on targets of energy homeostasis and apoptosis assessed the initial viability of PG and TMZ for neuroprotection. Animal experimentation with MCA induced ischemia-reperfusion (I/R) injury in rats was performed on five randomized groups. Sham operated control group received vehicle (saline) while the other four I-R groups were pre-treated with vehicle (saline), PG (8 â€‹mg/kg), TMZ treated (25 â€‹mg/kg), and PG â€‹+ â€‹TMZ (8 and 25 â€‹mg/kg) for 7 days by intraperitoneal route. Neurological deficit, infarct volume, and oxidative stress were evaluated to assess the extent of injury in rats. Inflammatory reactivity and apoptotic activity were determined with alterations in myeloperoxidase (MPO) activity, blood-brain barrier (BBB) permeability, and DNA fragments. Reperfusion injury inflicted cerebral infarct, neurological deficit, and shattered BBB integrity. The combination treatment of PG and TMZ restricted cellular damage indicated by significant (p â€‹< â€‹0.05) decrease in infarct volume and improvement in free radical scavenging ability (SOD activity and GSH level). MPO activity and LPO decreased which contributed in improved BBB integrity in treated rats. We speculate that inhibition of inflammatory and optimum energy utilization would critically contribute to observed neuroprotection with combined PG and TMZ treatment. Further exploration of this neuroprotective approach for post-recovery cognitive improvement is worth investigating.

Finding potent inhibitors for COVID-19 main protease (Mpro): an in silico approach using SARS-CoV-3CL protease inhibitors for combating CORONA.

SARS-CoV-2 is liable for the worldwide coronavirus disease (COVID-19) exigency. This pandemic created the need for all viable treatment strategies available in the market. In this scenario, computer-aided drug design techniques can be efficiently applied for the quick identification of promising drug repurposing candidates. In the current study, we applied the molecular docking approach in conjugation with molecular dynamics (MD) simulations to find out potential inhibitors against Mpro of SARS-CoV-2 from previously reported SARS-3CL protease inhibitors. Our results showed that N-substituted isatin derivatives and pyrazolone compounds could be used as a potent inhibitor and may possess an anti-viral activity against SARS-CoV-2. However, further experimental investigation and validation of the selected hits are required to find out their suitability for clinical trials. Communicated by Ramaswamy H. Sarma.

Synthesis and anticonvulsant evaluation of some novel 2,5-disubstituted 1,3,4-thiadiazoles: pharmacophore model studies.

A novel series of N'-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-(4-substituted benzaldehyde)-semicarbazones, N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl)ethanone]-semicarbazones and N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazones were synthesized and evaluated for their anticonvulsant potential using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPFZ) models. The minimal motor impairment (neurotoxicity) was determined by rotorod test. The results of the present study confirmed the requirements of various structural features of four binding site pharmacophore model for anticonvulsant activity.

Design, synthesis and biological evaluation of some novel benzimidazole derivatives for their potential anticonvulsant activity.

Selective GABA(A) receptor ligands are widely used clinically to reduce the occurrence of convulsions. Hence there is an intense interest in developing new benzimidazole derivatives demonstrating high selectivity and high affinity for GABA(A) receptors. With the purpose of designing new chemical entities with an enhanced binding affinity for GABA(A)/BZd receptor complex, we carried out a QSAR study on benzotriazine derivatives. We studied 28 potent GABA(A) receptor ligands; derivatives of benzotriazines, using a combination of various tested physicochemical, steric, electronic and thermodynamic descriptors to determine the quantitative correlation between binding affinity and structural features. The developed and validated final model showed a good correlative and predictive ability expressed by a squared correlation co-efficient (r(2)) of 0.954. The equation indicated that the binding affinity is strongly dependent upon the thermodynamic properties (CDE, DDE and PC). Correlation between these properties and anticonvulsant activity was used to synthesize compounds possessing potent anticonvulsant activity. Most of the compounds showed an ability to inhibit the maximum electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Compound 1A, i.e. 2-(4-Chloro-phenyl)-5-nitro-1H-benzimidazole exhibited maximum activity in both the convulsion models.