Investigating the antiviral therapeutic potentialities of marine polycyclic lamellarin pyrrole alkaloids as promising inhibitors for SARS-CoV-2 and Zika main proteases (Mpro)

<p>The new coronavirus variant (SARS-CoV-2) and Zika virus are two world-wide health pandemics. Along history, natural products-based drugs have always crucially recognized as a main source of valuable medications. Considering the SARS-CoV-2 and Zika main proteases (<b>Mpro</b>) as the re-production key element of the viral cycle and its main target, herein we report an intensive computer-aided virtual screening for a focused list of 39 marine lamellarins pyrrole alkaloids, against SARS-CoV-2 and Zika main proteases (<b>Mpro</b>) using a set of combined modern computational methodologies including molecular docking (<b>MDock</b>), molecule dynamic simulations (<b>MDS</b>) and structure-activity relationships (<b>SARs</b>) as well. Indeed, the molecular docking studies had revealed four promising marine alkaloids including [lamellarin H (<b>14</b>)/K (<b>17</b>)] and [lamellarin S (<b>26</b>)/Z (<b>39</b>)], according to their notable ligand-protein energy scores and relevant binding affinities with the SARS-CoV-2 and Zika (<b>Mpro</b>) pocket residues, respectively. Consequentially, these four chemical hits were further examined thermodynamically though investigating their <b>MD</b> simulations at 100 ns, where they showed prominent stability within the accommodated (<b>Mpro</b>) pockets. Moreover, in-deep SARs studies suggested the crucial roles of the rigid fused polycyclic ring system, particularly aromatic A- and F- rings, position of the phenolic -OH and δ-lactone functionalities as essential structural and pharmacophoric features. Finally, these four promising lamellarins alkaloids were investigated for their <i>in-silico</i> ADME using the SWISS ADME platform, where they displayed appropriated drug-likeness properties. Such motivating outcomes are greatly recommending further <i>in vitro/vivo</i> examinations regarding those lamellarins pyrrole alkaloids (<b>LPAs</b>).</p> <p>Communicated by Ramaswamy H. Sarma</p>