Since 2019 the world has seen severe onslaught of SARS-CoV-2 viral pandemic. There is an urgent need for drugs that can be used to either prevent or treat the potentially fatal disease COVD-19. To this end, we screened FDA approved antiviral drugs which could be repurposed for COVID-19 through molecular docking approach in the various active sites of receptor binding domain (RBD). The RBD domain of SARS-CoV-2 spike protein is a promising drug target due to its pivotal role in viral-host attachment. Specifically, we focussed on identifying antiviral drugs which could a) block the entry of virus into host cells, b) demonstrate anti-inflammatory and/or anti-thrombogenic properties. Drugs which poses both properties could be useful for prevention and treatment of the disease. While we prioritized a few antiviral drugs based on molecular docking, corroboration with in vitro studies including a new 3D human vascular lung model strongly supported the potential of Homoharringtonine, a drug approved for chronic myeloid leukaemia to be repurposed for COVID-19. This natural product drug not only antagonized the biding of SARS-CoV-2 spike protein RBD binding to human angiotensin receptor 2 (ACE-2) protein but also demonstrated for the first time anti-thrombogenic and anti-leukocyte adhesive properties in a human cell model system. Overall, this work provides an important lead for development of rapid treatment of COVID-19 and also establishes a screening paradigm using molecular modelling and 3D human vascular lung model of disease to identify drugs with multiple desirable properties for prevention and treatment of COVID-19.

COVID-19 pandemic has ravaged the world and vaccines have been rapidly developed as preventive measures. But there is no target-based therapy which can be used if infection sets in. Remdesiver and dexamethasone were not designed to combat COVID-19 but are used clinically till better targeted therapies are available. Given this situation target based therapies that intervene in the disease pathway are urgently needed. Since COVID-19 genesis is driven by uncontrolled inflammation and thrombosis and protein kinases are critical in mounting this response, we explored if available tyrosine kinase inhibitors (TKI) can be used as intervention. We profiled four TKI namely Lapatinib, Dasatinib, Pazopanib and Sitravatinib which inhibit tyrosine kinases but are completely distinct in their chemical structures. We demonstrate using in silico and an in vitro 3D-human vascular lung model which profiles anti-inflammatory and anti-thrombogenic properties that all four TKI are active in varying degrees. Our findings that chemically different TKI which share kinase inhibition as the common mechanism of action are active, strongly indicates that it is a tyrosine kinase target-based activity and not off-target arbitrary effect. We propose that TKI, approved for human use and widely available, can be rapidly deployed as specific target-based therapy for COVID-19.

Pre diabetes and type 2 diabetes are increasingly becoming rampant world wide. While there are medications to control blood glucose in type 2 diabetics, currently there are no interventions prescribed for pre diabetes. Alternate strategies to control blood glucose are needed either to act alone in pre diabetes or as supplement to the existing drugs for type 2 diabetes. We report here the targeting of critical molecular steps in muscle glucose uptake and metabolism to result in glucose lowering using a combination of safe vitamins. Our in vitro and in vivo data support the potential for using such vitamin combination for glucose control in pre diabetes and as a supplement in type 2 diabetics.

Nonlinear seismic analysis is becoming increasingly significant to grasp the performance of structures under earthquake. A nonlinear finite element model of existing bridge at Karad, India, including the bridge structure, pile groups, and the supporting foundation soil, is developed under 2D and 3D conditions in Gid (a pre and postprocessor software). The computational model is analyzed using Parallel OpenSees. OpenSees is open source software for carrying out earthquake engineering simulations, developed by Pacific Earthquake Engineering Research Centre, USA. The earthquake simulations were carried out using C-DAC's high performance computing facilities. The ground motion selection and modification technique-predicting median interstory drift response of building, ground motions are selected by M and R and scaling to Sa(T1), is used for seismic response of combined large scale soil-structure interaction of Karad bridge. The idealized model properly represents the actual geometry; boundary conditions, gravity loads and mass distribution. Nonlinear modeling and analysis allows more accurate determination of stresses, strains, deformations and forces of critical components. The present work involves the effects of specially varying input excitation (earthquakes) at an existing bridge site. A nonlinear finite element model of this bridge site including the bridge structure, pile group and supporting foundation soil is developed in 2D plane strain conditions and in 3D 20 noded brick element. Carefully calibrated nonlinear stress-strain models are employed for both bridge and soil materials, in order to realistically reproduce actual site conditions. Seismic input motions are defined as forces using the boundary layer force method (zero length element approach). The earthquake simulation of bridge structure includes large scale interaction between structure-foundation-soil system and deformations at various locations of the bridge. The results include deformations at base of piers and at various spans of the bridge. Performing the bridge simulation on C-DAC's Param Yuva facility results in accuracy and saving in computing efforts.

Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The RBD domain of SARS-CoV-2 Spike protein is a promising drug target due to its pivotal role in viral-host attachment. These specific structural domains can be targeted with small molecules or drug to disrupt the viral attachment to the host proteins. In this study, FDA approved Drugbank database were screened using a virtual screening approach and computational chemistry methods. Five drugs were short listed for further profiling based on docking score and binding energies. Further these selected drugs were tested for their in vitro biological activity. There was significant correlation between the prediction from computational studies and the actual RBD-ACE2 binding inhibition by the drugs. Then, we performed a series of studies that mimic some of the biological events seen in COVID-19 patients such as secretion of IL1β, presentation of a more thrombogenic endothelium by production of thrombomodulin and accumulation of inflammatory cells such as monocytes in the lungs. Of all the drugs, most promising drug was Ertugliflozin which is used for type-2 diabetes. This drug possesses several desired properties and may be a good candidate for immediate repurposing for treatment of COVID-19.