January 6, 2021
The COVID-19 outbreak is spreading alarmingly and the number of deaths is also increasing every day in some parts of the world.
Collaborative research and mobilization of scientific skills is needed to address the COVID-19 challenge. In continuation to collaborative research culture, Professor J. Jeyakanthan, Professor and Head, Department of Bioinformatics, Alagappa University, has jointly collaborated with Dr. Doc. N. Arul Murugan Docent in Theoretical Chemistry and Biology, Department of Theoretical Chemistry and Biology, School of Engineering Sciences in Chemistry, Biotechnology and Health KTH Royal Institute of Technology, Stockholm, Sweden, to refocus their research work to support frontline efforts in identifying the potent phytochemicals to treat COVID-19 infections.
In an international collaborative research to address the existing COVID-19 challenge, Prof. J. Jeyakanthan, has proposed a list of individual drugs and cocktails that deserve testing in clinical environment for treatment of COVID-19 and the results are published in Scientific Reports (https://doi.org/10.1038/s41598-020-75762-7). The researchers proposed a reliable double scoring approach to computationally screen lead drug-like compounds from DrugBank database against the most important SARS-CoV-2 viral targets, namely 3C-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp) and the spike (S) protein which play a major role in viral replication and human cell recognition.
They have identified a variety of as-yet-unexplored ways to attack COVID-19, in addition to proposing drug cocktails, namely Baloxavir marboxil, Natamycin and RU85053 can simultaneously inhibit multiple viral proteins based on binding free energies implemented in AutoDock Vina and molecular mechanics—generalized Born surface area approaches. SARS-CoV-2 is a rapidly mutating positive single strand RNA virus with as many as 12,000 mutations reported till now including a key mutation – D614G.
Therefore, this multi-targeting ability of drugs offers an effective route to deal with drug resistance which enables the drugs to work around the viral mutations. Accordingly, if a drug that can target several proteins and if one viral protein becomes mutated, the drug can still be effective on other viral proteins. This is the potency of multi-targeting drugs and drugs cocktails proposed in this article. In addition, the researchers have identified a few compounds such as Phthalocyanine, Tadalafl, Lonafarnib, Nilotinib, Dihydroergotamine and R-428 which can bind to all the specified viral targets simultaneously and can serve as multi-targeting drugs. Further, their study also included the binding energy estimation for various compounds which are currently under drug trials.
It is shown that Remdesivir binds to RdRp and 3CLpro with high binding affinity indicating that it can be categorized as a multi-targeting drug. Baricitinib and Umifenovir were found to be compounds with superior target-specific binding while Darunavir is found again to be a multi-targeting drug.
Double scoring approach also explains why some drugs like hydroxychloroquine and Oseltamivir are not very active against any of the viral targets and in particular, the former compound has only moderate binding affinity or inhibition potential towards RdRp. Among the drugs that the study recommended for testing were Tivantinib, Olaparib, Zoliflodacin, Golvatinib, Sonidegib, Regorafenib and PCO-371. The paper also provides a listing of multi-targeting drugs such as DB04016, Phthalocyanine and Tadalafil which can also be effective in combating the rapidly mutating coronavirus.
More details about this research work can be found at: Searching for target-specific and multi-targeting organics for Covid-19 in the Drugbank database with a double scoring approach. Scientific reports. https://doi.org/10.1038/s41598-020-75762-7