Unipd studies the mechanism of action between antiviral drugs and the SARS-CoV-2 main protease


Identifying a new drug is a timely and complex process, taking an average of ten years to complete, and includes substantial economic resources and various transversal scientific skills. Reducing the amount of time needed to identify a new drug, especially in a scenario such as the current Covid-19 pandemic, would be enormously beneficial. Recent developments in information technology together with advances in pharmaceutical chemistry have led to "simulating the entire recognition process between a drug and its molecular target." As such, using an accurate virtual replication, the goal is to precisely understand what happens in the human body and then translate results into therapeutic action.

The Molecular Modeling Section (MMS) of the Department of Pharmaceutical and Pharmacological Sciences at the University of Padua has developed, under a reasonable timeline and with a high level of accuracy, a methodology that follows the path of a drug as it encounters and recognizes a particular region of a molecular target in order for it to perform its function.

Led by Prof Stefano Moro and his team from the Department of Pharmaceutical and Pharmacological Sciences, the work published in "Scientific Reports" is based on the mechanism of action of a drug at the molecular level and entitled, Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir (Giovanni Bolcato, Maicol Bissaro, Matteo Pavan, Mattia Sturlese, & Stefano Moro).

To date, no molecular details are available regarding the mechanism of action of antiviral drugs that support a clinical use to fight the Covid-19 emergency. Historically, the treatment strategy is to use previous clinical evidence to prove effectiveness in other pathologies and then apply this under new contexts during a pandemic. Pre-approved pharmacological treatments for other viral infections were used against the virus during the first wave of the SARS-CoV-2 emergency, setting a base for the treatment of Covid-19. Taking advantage of evidence discovered during the first coronavirus pandemic (SARS, 2002-2003), doctors have adopted a therapeutic approach using HIV antiretroviral drugs. Doctors gathered the positive preliminary indications on the effectiveness of the treatment while waiting for an effective vaccine.

Prof. Stefano Moro explains, "The particular technique that was developed in our laboratory is called supervised molecular dynamics (SuMD). This technique has found its application, in the midst of the SARS-CoV-2 coronavirus pandemic, by describing the molecular recognition between the main protease Mpro, an important virus protein, and three drugs previously used in the clinical setting for the pathological treatment of viral infections. Of the three drugs used, the molecular description of their mechanism of action with the Mpro protease was still unknown.” This technique allows us to follow how the drug approaches its target protein over time, as well as in which region the surface recognition occurs, and what recognizable chemical property of the drug carries out its success.

PhD students Giovanni Bolcato and Maicol Bissaro from MMS of the Department of Pharmaceutical and Pharmacological Sciences explain, “In addition to interpreting, at an atomic level, the mechanism recognized between the three drugs (Lopinavir, Ritonavir and Nelfinavir) and where the Mpro protease takes place, the application of this methodology lays the foundations for a new phase of potential drug designs for the same viral protein and other proteins needed during the SARS-CoV-2 replication cycle. This computational technique allows us to suggest new chemical structures that present better therapeutic efficacy as well as reducing possible side effects on the body. The main result of using this methodology will be to support experimental studies in identifying the early stage of all the possible drug candidates and the optimal characteristics for an efficient recognition of the molecular target. Not only that, it will be possible to decrease the number of chemical compounds needed to introduce into the supply chain for the development of a new drug, consequently reducing time and costs. Finally, it will be possible to have preliminary, yet accurate, indications of the potential toxicity profile of these drugs by applying the same methodology to the proteins that should not be simultaneously recognized by the same compound and which must therefore maintain their functionality even during the start and during the development of the disease."