COVID19@MMS: Targeting the Coronavirus SARS-CoV-2: computational insights into the mechanism of action ofthe protease inhibitors Lopinavir, Ritonavir,and Nelfinavir. | |
Topic hints: | Coronavirus SARS-CoV-2 is a recently discovered single-stranded RNA (ssRNA) betacoronavirus, responsible for a severe respiratory disease known as coronavirus disease 2019 (COVID-19), which is rapidly spreading. Chinese health authorities, as a response to the lack of an effective therapeutic strategy, started to investigate the use of lopinavir and ritonavir, previously optimized for the treatment and prevention of HIV/AIDS viral infection. Despite the clinical use of these two drugs, no information regarding their possible mechanism of action at the molecular level is still known for SARS-CoV-2. Very recently, the crystallographic structure of the SARS-CoV-2 main protease (Mpro), also known as C30 Endopeptidase, was published. Starting from this essential structural information, in the present work we have exploited Supervised Molecular Dynamics (SuMD), an emerging computational technique that allows investigating at an atomic level the recognition process of a ligand from its unbound to the final bound state. In this research, we provided molecular insight on the whole interaction pathway of lopinavir, ritonavir, and nelfinavir, three potential C30 Endopeptidase inhibitors, with the last one taken into consideration due to the promising in-vitro activity shown against the structurally related SARS-CoV protease. |
| Work in Progress: |  |
Collaborators: | Barbara Gatto, Alice Sosic - DSF, UNIPD Massimo Bellanda, Roberto Battistutta - DiSC, UNIPD Cristiano Salata - DMM, UNIPD |
Pubblication |
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Video 1: Lopinavir binding pathway against SARS-CoV-2 main protease. The video is composed of four synchronized and animated panels that summarized a putative molecular recognition mechanism of HIV protease inhibitor Lopinavir against SARS-CoV-2 main protease. In the first panel (upper-left), the SuMD binding trajectory is reported. The backbone of SARS-CoV-2 main protease is represented using ribbon style (pink colour) and the protein residues within 4 Å of Lopinavir (rendered by green carbon atoms) are dynamically shown. In the second panel (upper-right), the distance between the inhibitor center of mass (CM) and the protein catalytic binding site during the entire trajectory is reported. The time evolution is reported in a ns scale. In the third panel (lower-left), the MMGBSA energy profile describing the binding event is reported. In the fourth panel (lower-right) cumulative electrostatic interactions are reported for the 15 protease residues most contacted by Lopinavir during the whole binding simulation. |  | |
Video 2: Ritonavir binding pathway against SARS-CoV-2 main protease. The video is composed of four synchronized and animated panels that summarized a putative molecular recognition mechanism of HIV protease inhibitor Ritonavir against SARS-CoV-2 main protease. In the first panel (upper-left), the SuMD binding trajectory is reported. The backbone of SARS-CoV-2 main protease is represented using ribbon style (pink colour) and the protein residues within 4 Å of Ritonavir (rendered by orange carbon atoms) are dynamically shown. In the second panel (upper-right), the distance between the inhibitor center of mass (CM) and the protein catalytic binding site during the entire trajectory is reported. The time evolution is reported in a ns scale. In the third panel (lower-left), the MMGBSA energy profile describing the binding event is reported. In the fourth panel (lower-right) cumulative electrostatic interactions are reported for the 15 protease residues most contacted by Ritonavir during the whole binding simulation. |  | |
Video 3: Nelfinavir binding pathway against SARS-CoV-2 main protease. The video is composed of four synchronized and animated panels that summarized a putative molecular recognition mechanism of HIV protease inhibitor Nelfinavir against SARS-CoV-2 main protease. In the first panel (upper-left), the SuMD binding trajectory is reported. The backbone of SARS-CoV-2 main protease is represented using ribbon style (pink colour) and the protein residues within 4 Å of Nelfinavir (rendered by cyan carbon atoms) are dynamically shown. In the second panel (upper-right), the distance between the inhibitor center of mass (CM) and the protein catalytic binding site during the entire trajectory is reported. The time evolution is reported in a ns scale. In the third panel (lower-left), the MMGBSA energy profile describing the binding event is reported. In the fourth panel (lower-right) cumulative electrostatic interactions are reported for the 15 protease residues most contacted by Nelfinavir during the whole binding simulation. |  | |