In-silico screening and molecular dynamics simulation of quinazolinone derivatives as PARP1 and STAT3 dual inhibitors: a novel DML approaches.

Modern cancer therapy now routinely employs the blocking of many oncoproteins or pathways. With two or more medicines, multiple inhibitions are often accomplished via DML techniques. In this study, we developed 30 quinazolinone derivatives as PARP1 and STAT3 dual inhibitors using DML methods and these compounds were tested for their dual inhibitory effect on PARP1 and STAT3 using docking, MM-GBSA, and molecular dynamics simulation investigations. The docking studies of ligands against PARP1 and STAT3 were performed using the Glide module, in silico ADMET screening was performed using the quickprob module, binding energy calculation was performed using the Prime MM-GBSA module, MD simulation was performed using the Desmond module, and atomic charges were calculated using the Jaguar module of Schrodinger suite 2019-4. Of the substances studied, the derivative 1f has a considerable gliding score. The in silico ADMET characteristics are within the approved range. PRIME MM-GB/SA was used to compute the binding free energy, and the results are substantial. To investigate the dynamic behavior of the protein-ligand complex, compound 1f was subjected to MD simulation at 100 ns. The tested chemical 1f produced the greatest results in MD simulations and MM-GBSA calculations, indicating that this ligand can inhibit more effectively.Communicated by Ramaswamy H. Sarma.

Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: a prospective study.

PURPOSE: To evaluate the role of intermittent prophylaxis with clobazam in the management of HWE in a long-term prospective study. MATERIAL AND METHODS: Two hundred and sixty patients [M:F - 194:66] with HWE were recruited. Patients were divided into: (a) 'HWE alone' (n=198) - received intermittent clobazam prophylaxis, 1-1½h prior to hot water head bath (group A); (b) 62 patients (20.4%) with 'HWE with spontaneous seizures were treated with continuous AEDs along with intermittent clobazam therapy (group B). RESULTS: Patients (n=198) in group A was followed for mean of 17.6 ± 10.6 months (range: 3-57). One hundred and forty seven patients (74.2%) had excellent response with complete seizure freedom with clobazam therapy while 12 (6.1%) had >75% reduction in seizure frequency. Remaining 39 (19.7%) required additional standard AED along with clobazam and 18 patients among them developed spontaneous/unprovoked seizure at follow up of 6.7 ± 4.1 months. Forty five patients in group B were seizure free while on continuous AEDs. CONCLUSIONS: Intermittent clobazam prophylaxis prior to head water bath might be a preferred mode of treatment of pure HWE. Additional AEDs are required if they have associated non-reflex unprovoked seizure.

Idiopathic generalized epilepsy: Phenotypic and electroencephalographic observations in a large cohort from South India.

PURPOSE: We studied the phenotype and electroencephalographic (EEG) features, and therapeutic aspects of idiopathic generalized epilepsies (IGEs) in South Indian population. PATIENTS AND METHODS: This prospective cross-sectional hospital-based study was carried out on non-consecutive 287 patients (age 22.2 ± 7.7 years; M:F = 139:148) with IGE syndrome. Their clinical and EEG observations were analyzed. RESULTS: Majority of the patients had onset of seizures <20 years of age (n = 178; 62%). Thirty one patients (10.8%) had family history of epilepsy. Nearly half of them (49.9%) had <5 years of duration of seizures. The type of IGEs included Juvenile myoclonic epilepsy (JME): 115 (40.1%); IGE with generalized tonic-clonic seizures (GTCS) only: 102 (39.02%); childhood absence epilepsy (CAE): 35 (12.2%); GTCS on awakening: 15 (5.2%); Juvenile absence epilepsy (JAE): 11 (3.8%); and unclassified seizures: 9 (3.1%). The triggering factors noted in 45% were sleep deprivation (20%), non-compliance and stress in 5% each. The EEG (n = 280) showed epileptiform discharges in about 50% of patients. Epileptiform discharges during activation was observed in 40/249 patients (16.1%): Hyperventilation in 32 (12.8%) and photic stimulation in 19 (7.6%). The seizures were well controlled with anti-epileptic drugs (AEDs) in 232 (80.8%) patients and among them, 225 (78.4%) patients were on monotherapy. Valproate (n = 131) was the most frequently prescribed as monotherapy. CONCLUSIONS: This is one of the largest cohort of patients with IGE. This study reiterates the importance of segregating IGE syndrome and such analysis will aid to the current understanding and management.

Glycosaminoglycan-mediated selective changes in the aggregation states, zeta potentials, and intrinsic stability of liposomes.

Though the aggregation of glycosaminoglycans (GAGs) in the presence of liposomes and divalent cations has been previously reported, the effects of different GAG species and minor changes in GAG composition on the aggregates that are formed are yet unknown. If minor changes in GAG composition produce observable changes in the liposome aggregate diameter or zeta potential, such a phenomenon may be used to detect potentially dangerous oversulfated contaminants in heparin. We studied the mechanism of the interactions between heparin and its oversulfated glycosaminoglycan contaminants with liposomes. Herein, we demonstrate that Mg(2+) acts to shield the incoming glycosaminoglycans from the negatively charged phosphate groups of the phospholipids and that changes in the aggregate diameter and zeta potential are a function of the glycosaminoglycan species and concentration as well as the liposome bilayer composition. These observations are supported by TEM studies. We have shown that the organizational states of the liposome bilayers are influenced by the presence of GAG and excess Mg(2+), resulting in a stabilizing effect that increases the T(m) value of DSPC liposomes; the magnitude of this effect is also dependent on the GAG species and concentration present. There is an inverse relationship between the percent change in aggregate diameter and the percent change in aggregate zeta potential as a function of GAG concentration in solution. Finally, we demonstrate that the diameter and zeta potential changes in POPC liposome aggregates in the presence of different oversulfated heparin contaminants at low concentrations allow for an accurate detection of oversulfated chondroitin sulfate at concentrations of as low as 1 mol %.