COVID-19 represents a new potentially life-threatening illness caused by severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 pathogen. In 2021, new variants of the virus with multiple key mutations have emerged, such as B.1.1.7, B.1.351, P.1 and B.1.617, and are threatening to render available vaccines or potential drugs ineffective. In this regard, we highlight 3CLpro, the main viral protease, as a valuable therapeutic target that possesses no mutations in the described pandemically relevant variants. 3CLpro could therefore provide trans-variant effectiveness that is supported by structural studies and possesses readily available biological evaluation experiments. With this in mind, we performed a high throughput virtual screening experiment using CmDock and the “In-Stock” chemical library to prepare prioritisation lists of compounds for further studies. We coupled the virtual screening experiment to a machine learning-supported classification and activity regression study to bring maximal enrichment and available structural data on known 3CLpro inhibitors to the prepared focused libraries. All virtual screening hits are classified according to 3CLpro inhibitor, viral cysteine protease or remaining chemical space based on the calculated set of 208 chemical descriptors. Last but not least, we analysed if the current set of 3CLpro inhibitors could be used in activity prediction and observed that the field of 3CLpro inhibitors is drastically under-represented compared to the chemical space of viral cysteine protease inhibitors. We postulate that this methodology of 3CLpro inhibitor library preparation and compound prioritisation far surpass the selection of compounds from available commercial “corona focused libraries”.
The Zaire Ebola viral protein VP24 selectively inhibits nuclear import of STAT1 and as such blocks interferon-induced antiviral responses vital for cell's emergency. Inhibition of VP24 with small molecule inhibitor may neutralize the threatening action of Ebola virus. We performed molecular docking of compounds from a selected small library of plant polyphenols on to VP24. Our research shows that 1,2,3,6-tetragalloyl glucose, epigallocatechin gallate, chlorogenic acic, oleuropein and miquelianin represent promising leads for further studies.
The recent outbreak of Ebola viral disease (EVD) in West Africa reminded us that an effective anti-viral treatment still does not exist, despite the significant progress that has recently been made in understanding biology and pathology of this lethal disease. Currently, there are no approved vaccine and/or prophylactic medication for the treatment of EVD in the market. However, the serious pandemic potential of EVD mobilized research teams in the academy and the pharmaceutical industry in the effort to find an Ebola cure as fast as possible. In this chapter, we are giving the condensed review of different approaches and strategies in search of a drug against Ebola. We have been focusing on the review of the targets that could be used for in silico, in vitro, and/or in vivo drug design of compounds that interact with the targets in different phases of the Ebola virus life cycle.
SARS-CoV-2 belongs to the family of coronaviruses, which are characterized by spikes that sit densely on the surface of the virus. The spike protein (Spro) is responsible for the attachment of the virus to the host cell via the ACE2 receptor on the surface of the host cell. The strength of the interaction between the receptor-binding domain (RBD) of the highly glycosylated spike protein of the virus and the host cell ACE2 receptor represents the key determinant of the infectivity of the virus. The SARS-CoV-2 virus has mutated since the beginning of the outbreak, and the vast majority of mutations has been detected in the spike protein or its RBD. Since specific mutations significantly affect the ability of the virus to transmit and to evade immune response, studies of these mutations are critical. We investigate GISAID data to show how viral spike protein mutations evolved during the pandemic. We further present the interactions of the viral Spro RBD with the host ACE2 receptor. We have performed a large-scale mutagenesis study of the Spro RBD-ACE2 interface by performing point mutations in silico and identifying the ambiguous interface stabilization by the most common point mutations in the viral variants of interest (beta, gamma, delta, omicron).
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