3/6/2020 8:04:16 AM
Is There Any Hope For A Drug That Defeats COVID-19?
COVID-19, a Viral Outbreak That Started In Wuhan, Hubei Province, China and Now Becoming a Worldwide Nightmare. News Report Of The Increase In The Number Of The Infected People And Deaths Related To This Virus Every Day! Is There Any Hope For A Novel Treatment? Join Us With This #UQR21 To Know More
When an emergent infection occurs the drug companies and the scientists try to find its appropriate drugs as fast as possible to manage the outbreaks. Computational drug repurposing method is one form of these rapid solutions that solely depends on previously synthesized drugs.
The first step in this method and any other method that seeks for a drug of a new disease, is to know the structure and the pathogenesis of the virus very well. Researchers would then try to look for a drug target, which is usually part of the virus that plays a crucial role in pathogenesis while being highly preserved, so that it is less subject to genetic mutations. If the appropriate target is selected, it usually guarantees the effectiveness of the drug and a better tolerance of the vaccine product towards the viral resistance phenomena.
After proper target selection, scientists try to make a computational model of that target or they just use a previous model that is identical to the target (homologous model). A comprehensive search is then initiated in drug banks and databases to find the best molecular options that suit the target chemically, and hopefully is not a toxin, neurotoxic agent, or anti-tumoral agent! After the preliminary screening, researcher then eliminate the drugs that are not approved and apply kinetic and biomedical analyses to narrow down their options to a few known drugs.
At the end of this journey our heroes have ended up with 6 agents: Nelfinavir, Praziquantel, Pitavastatin, Perampanel, Eszopiclone, and Zopiclone, which have good binding modes and are selected for further analysis. Their target binding free energy is calculated and Nelfinavir is selected as the most promising candidate! Moment of truth: it does not fit the target completely.
Don’t worry! The story does not end here! Scientists have another method which has more novelty and also uses artificial intelligence. Target selection is performed exactly like the previous method, whilst the other steps are quite different.
Using this method, researchers of the Insilico Medicine Company have chosen the C30 Endopeptidase, also referred to as the 3C-like proteinase or coronavirus 3C-like protease (3CLP) or coronavirus main protease (Mpro) as their target. 3CLP is a homodimeric cysteine protease and a member of a family of enzymes found in the Coronavirus polyprotein. It cleaves the polyproteins into individual polypeptides that are required for replication and transcription. Following the translation of the messenger RNA to yield the polyproteins, the 3CLP is auto-cleaved from the polyproteins to form a mature enzyme, and then cleaves all the 11 remaining downstream non-structural proteins. No doubt that 3CLP plays a central role in the viral replication cycle and is an attractive target against the human SARS virus, corona’s young ancestor, too!
The next pipeline, and possibly our last hope, is the small molecule drug discovery. When selected, the target is put into 3 models which are crystal structure, homology model and co-crystalized ligand. All of these models are then matched to the best chemical molecules that fit them using a deep learning approach. The final step is familiar, chemical calculations and analysis are performed to predict the effectiveness and the efficacy of the compounds as drugs. Using the search engine on the ChEMBL website the highest similarity rate that has been found for any of the COVID-19 targets is 80%!
Researchers frequently repeat these steps until they find the best structures that suit the current situation. After all of these steps researchers synthesize the most efficient structures and take them to the next pipeline which is a predictors of clinical trial outcomes.
Fingers are crossed for the Insilico Medicine’s drug discovery which is now awaiting the approval for their last pipeline to bless us and the whole world an effective solution for COVID-19!
USERN Junior Ambassador, Bahrain