Jaya Bandyopadhyay

Multi-target screening mines hesperidin as a multi-potent inhibitor: Implication in Alzheimer's disease therapeutics

Alzheimers disease (AD) is the most frequent form of neurodegenerative disorder in elderly people. Involvement of several pathogenic events and their interconnections make this disease a complex disorder. Therefore, designing compounds that can inhibit multiple toxic pathways is the most attractive therapeutic strategy in complex disorders like AD. Here, we have designed a multi-tier screening protocol combining ensemble docking to mine BACE1 inhibitor, as well as 2-D QSAR models for anti-amyloidogenic and antioxidant activities. An in house developed phytochemical library of 200 phytochemicals has been screened through this multi-target procedure which mine hesperidin, a flavanone glycoside commonly found in citrus food items, as a multi-potent phytochemical in AD therapeutics. Steady-state and time-resolved fluorescence spectroscopy reveal that binding of hesperidin to the active site of BACE1 induces a conformational transition of the protein from open to closed form. Hesperidin docks close to the catalytic aspartate residues and orients itself in a way that blocks the cavity opening thereby precluding substrate binding. Hesperidin is a high affinity BACE1 inhibitor and only 500xa0nM of the compound shows complete inhibition of the enzyme activity. Furthermore, ANS and Thioflavin-T binding assay show that hesperidin completely inhibits the amyloid fibril formation which is further supported by atomic force microscopy. Hesperidin exhibits moderate ABTS(+) radical scavenging assay but strong hydroxyl radical scavenging ability, as evident from DNA nicking assay. Present study demonstrates the applicability of a novel multi-target screening procedure to mine multi-potent agents from natural origin for AD therapeutics.

Biogenic synthesis of silver nanoparticles from Cassia fistula (Linn.): In vitro assessment of their antioxidant, antimicrobial and cytotoxic activities

The present study reports on biogenic-synthesised silver nanoparticles (AgNPs) derived by treating Ag ions with an extract of Cassia fistula leaf, a popular Indian medicinal plant found in natural habitation. The progress of biogenic synthesis was monitored time to time using a ultraviolet-visible spectroscopy. The effect of phytochemicals present in C. fistula including flavonoids, tannins, phenolic compounds and alkaloids on the homogeneous growth of AgNPs was investigated by Fourier-transform infrared spectroscopy. The dynamic light scattering studies have revealed an average size and surface Zeta potential of the NPs as, -39.5 nm and -21.6 mV, respectively. The potential antibacterial and antifungal activities of the AgNPs were evaluated against Bacillus subtilis, Staphylococcus aureus, Candida kruseii and Trichophyton mentagrophytes. Moreover, their strong antioxidant capability was determined by radical scavenging methods (1,1-diphenyl-2-picryl-hydrazil assay). Furthermore, the AgNPs displayed an effective cytotoxicity against A-431 skin cancer cell line by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, with the inhibitory concentration (IC50) predicted as, 92.2 ± 1.2 μg/ml. The biogenically derived AgNPs could find immense scope as antimicrobial, antioxidant and anticancer agents apart from their potential use in chemical sensors and translational medicine.

Multi-functional neuroprotective activity of neohesperidin dihydrochalcone: a novel scaffold for Alzheimer's disease therapeutics identified via drug repurposing screening

Alzheimers disease (AD) is a complex neurological disorder where many pathogenic signaling cascades are simultaneously activated. Moreover, their inter-relations and molecular reasons for activations are not completely understood, which impedes the development of therapeutics for AD. Multi-target drug discovery has recently come into prominence, particularly in the case of AD, due to the ability of the potential hits to simultaneously inhibit many pathways causing the disease. The present study reports the application of an FDA approved sweetener, neohesperidin dihydrochalcone (NHD), as a multi-target inhibitor for AD therapeutics. NHD shows a high BACE1 and amyloid aggregation inhibition ability as well as strong anti-oxidant activity. NHD binds to the active site of BACE1 and thus induces a conformational transition to a closed complex, which excludes substrate recognition, evident from steady-state and time-resolved fluorescence spectroscopy. 500 nM NHD completely inhibits the activity of BACE1. 8-Anilino-1-naphthalenesulfonic acid (ANS), Thioflavin-T fluorescence assay and Atomic Force Microscopy (AFM) studies confirm that co-incubation of equimolar NHD with Aβ25–35 almost completely inhibits Aβ25–35 fibril formation. Co-incubation of NHD with Aβ25–35 entirely alleviates the neurotoxic effects of equimolar Aβ25–35. NHD dose-dependently inhibits Aβ25–35 induced cellular ROS generation. In vitro bio-assays confirm that NHD is itself a strong anti-oxidant and shows scavenging activity against a wide variety of radicals. Our results clearly indicate that NHD changes the aggregation pathways of Aβ in such a way that the formations of toxic oligomeric/fibrillar forms are reduced significantly. The present study demonstrates the multi-target inhibitory potency of NHD in AD therapeutics identified via drug repurposing screening.

Observation of the unconventional optoelectronic properties of silicon conjugated graphene nanosheets

Graphene has been realized for its significant physico-chemical properties. The extraordinary surface area and high electronical conductivity of graphene makes it a potential candidate in the field of nanoelectronics and sensors. In this study, graphene has been conjugated with silicon and its different physical and chemical properties were evaluated. The total energy of the composite system came out to be −6111.62 eV. Chemical potential of the composite system exhibits ∼ 5.64 eV. DOS calculations for composite of silicon and graphene came out to be ∼ 17 eV−1 for the applied bias voltage of 40 eV, as when compared to higher values of DOS for monolayer silicon and graphene nanosheets. Silicon is widely known to exhibit semiconducting behavior and has already been used in fabricating various CMOS devices. In this present work, we try to study the outcome of the conjugation of graphene nanosheets with silicon nanosheets in different combinations. Understanding the interactions between two semiconducting materials could shed some light in the underlying physical and chemical interaction which would help in devising novel optoelectronic systems.

Unraveling the temperature dependent elastic properties of Stone-Wales defect induced single-walled carbon nanotube

Elastic properties of a material dictate how much it will compress under extrinsic stress and determine the net stiffness of a material. In the present study, employing molecular dynamics simulation, calculation of the Youngs modulus and its relation with elasticity of the material has been performed at different temperature ranges varying from 4oC (277 K) to 2227oC (2500 K). Metallic SWCNT (5, 5) and semiconductor SWCNT (7, 0) are selected as our experimental material. Gradual increase in temperature reduces rigidity and as well as decreases elasticity of the pristine nanotubes as evident from the gradual decrease in the Youngs modulus value. But Stone-Wales defect induced SWCNT retains the rigidity of the nanotubes even at higher temperature as evident from higher Youngs modulus value. Understanding the stress-strain relation at different temperature ranges for SWCNT would help us in exploring its mechanical properties and in turn designing devices of ultra-high stiffness at higher temperature, finding its applications from aerospace to medical diagnostics.