Identification of a repurposed drug as an inhibitor of Spike protein of human coronavirus SARS-CoV-2 by computational methods

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causessevere respiratory disease. SARS-CoV-2 is responsible for the outbreak of COVID-19 pandemic worldwide.As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19,discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylatedSpike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptorthrough the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and isessential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviraltherapy and vaccine development. In silico screening, docking, and molecular dynamics simulation studieswere performed to identify repurposing drugs using DrugBank and PubChem library against the RBD ofS-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment ofconstipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein–ACE2interface by making substantial p-p interactions with Tyr505 in the ‘Site 1’ hook region of RBD andhydrophilic interactions with Glu406, Ser494, and Thr500. Bisoxatin consistently binds to the proteinthroughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may bea promising repurposable drug molecule to develop new chemical libraries for inhibiting SARS-CoV-2 entryinto the host.

In vitro, in vivo and in silico anti-hyperglycemic inhibition by sinigrin

Objective To evaluate the anti-hyperglycemic potential of sinigrin using in vitro, in silico and in vivo streptozotocin (STZ) induced hyperglycemic zebrafish model. Methods The in vitro enzyme inhibition assay was carried out to determine the IC

In vitro, in vivo and in silico anti-hyperglycemic inhibition by sinigrin

OBJECTIVE@#To evaluate the anti-hyperglycemic potential of sinigrin using in vitro, in silico and in vivo streptozotocin (STZ) induced hyperglycemic zebrafish model.@*METHODS@#The in vitro enzyme inhibition assay was carried out to determine the IC value against α-glucosidase and α-amylase, in silico molecular docking was performed against both enzymes with PyRx tool and simulations were performed using GROMACS tool. Hyperglycemia was induced in zebrafishes using three intraperitoneal injections on alternating days for 1 week at 350 mg/kg of STZ. Hyperglycemic fishes were treated intraperitoneally with 50, 100 and 150 mg of sinigrin/kg of body weight for 24 h and glucose levels were measured.@*RESULTS@#The sinigrin showed very strong inhibition against α-glucosidase and α-amylase with 0.248 and 0.00124 μM while reference drug acarbose showed IC value of 73.0700 and 0.0017 μM against α-glucosidase and α-amylase, respectively. Kinetic analysis revealed that sinigrin has the mixed type mode of inhibition against α-glucosidase. Molecular docking results revealed its strong binding affinity with α-glucosidase (-10.00 kcal/mol) and α-amylase (-8.10 kcal/mol). Simulations graphs confirmed its stability against both enzymes. Furthermore, in hyperglycemic zebrafishes most significant (P < 0.001) reduction of glucose was occurred at 150 mg/kg, moderate significant reduction of glucose was observed at 100 mg/kg and no any significant reduction of glucose was measured at 50 mg/kg.@*CONCLUSIONS@#It can be evident from the present results that sinigrin has potent anti-hyperglycemic activity and it may prove to be effective treatment for the hyperglycemia.

Interaction of nucleic acids with carbon nanotubes and dendrimers.

Nucleic acid interaction with nanoscale objects like carbon nanotubes (CNTs) and dendrimers is of fundamental interest because of their potential application in CNT separation, gene therapy and antisense therapy. Combining nucleic acids with CNTs and dendrimers also opens the door towards controllable self-assembly to generate various supra-molecular and nano-structures with desired morphologies. The interaction between these nanoscale objects also serve as a model system for studying DNA compaction, which is a fundamental process in chromatin organization. By using fully atomistic simulations, here we report various aspects of the interactions and binding modes of DNA and small interfering RNA (siRNA) with CNTs, graphene and dendrimers. Our results give a microscopic picture and mechanism of the adsorption of single- and double-strand DNA (ssDNA and dsDNA) on CNT and graphene. The nucleic acid–CNT interaction is dominated by the dispersive van der Waals (vdW) interaction. In contrast, the complexation of DNA (both ssDNA and dsDNA) and siRNA with various generations of poly-amido-amine (PAMAM) dendrimers is governed by electrostatic interactions. Our results reveal that both the DNA and siRNA form stable complex with the PAMAM dendrimer at a physiological pH when the dendrimer is positively charged due to the protonation of the primary amines. The size and binding energy of the complex increase with increase in dendrimer generation. We also give a summary of the current status in these fields and discuss future prospects.