Pharmaceutical Sciences
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/30821
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Browsing Pharmaceutical Sciences by Author "Arachchige, Vindi Mahesha Jayasinghe"
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Item Allosteric Modulation of Small-Molecule Drugs on ACE2 Conformational Change upon Binding to SARS-CoV-2 Spike Protein(2022) Wang, Duen-Shian; Hayatshahi, Hamed; Arachchige, Vindi Mahesha JayasingheSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused Coronavirus disease (COVID-19) pandemic. Drug repurposing studies, including drugs such as dexamethasone (DEX), chloroquine (CQ), and telmisartan(TLS), have been performed in COVID-19 clinical trials. DEX and CQ have been demonstrated in vitro to bind angiotensin-converting enzyme 2 (ACE2), a cellular entry receptor utilized by SARS-CoV-2. However, how DEX/CQ bind to ACE2 and their mechanisms of action are still unknown. Here we demonstrated that DEX, CQ, and TLS disrupt the interactions between SARS-CoV-2 spike protein and human ACE2 via binding to an allosteric site close to the viral spike protein binding region at the peptidase domain of ACE2, causing a conformational change of the ACE2. We defined four conformational states of ACE2 based on the two helices distances. Our molecular dynamics simulations suggested that binding to the viral spike protein shifted ACE2 conformation populations away from "Open" conformation. Such conformation population shift is further enhanced by the Delta variant. The binding of the drugs to ACE2 rescues this conformation population shift allosterically to keep ACE2 in "Open" conformation mostly. Our findings provide a potential insight that modulating the conformation of ACE2 may prevent SARS-CoV-2 invasion due to unfavored poses for spike protein binding.Item Design of man-made miniature CRISPR-Cas systems using computational technologies(2022) Arachchige, Vindi Mahesha Jayasinghe; Liu, JinPurpose: An RNA-guided targeted genome engineering platform, CRISPR/Cas system is one of the breakthroughs of the twenty-first century. Despite the wealth of its advancement, there are some associated limitations that need to be overcome for the betterment of this revolutionized technology. Among them, the larger size of the available Cas proteins that are essential for the functioning of these tools limits their in vivo administration due to the low delivery efficiency. To address this issue, we have used computational chemistry tools to design smaller versions or compact size Cas proteins that can be used as an alternative. Methods: The available crystal structures of CRISPR-Cas systems were utilized and the reduction was done preserving the regions that are essential for the DNA binding and cleavage functions using Chimera, Yasara, and the Swiss Model software. Molecular Dynamics (MD) simulations were performed to obtain stable conformations of the reduced structures. The minimized sequences were used to generate their structures by the Swiss Model. Results/Conclusions: Four stable man-made miniature Cas proteins were generated that are less than half the size of the currently used CRISPR systems such as Cas9 or Cas12a. The sequence-based modeling studies using the Swiss model have shown the similar folding of these reduced proteins compared to their original counterparts. Further experimental validation of their ds-DNA cleavage activities remains to be determined at this point of the study.