Bioguided Isolation of Cyclopenin Analogues as Potential SARS-CoV-2 Mpro Inhibitors from Penicillium citrinum TDPEF34

Abstract

SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is effective in inhibiting SARS-CoV-2 remains a challenge. Natural products are the origin of many currently used pharmaceuticals and, for this reason, a library of in-house fungal extracts were screened to assess their potential to inhibit the main viral protease Mpro in vitro. The extract of Penicillium citrinum, TDPEF34, showed potential inhibition and was further analysed to identify potential Mpro inhibitors. Following bio-guided isolation, a series of benzodiazepine alkaloids cyclopenins with good-to-moderate activity against SARS-CoV-2 Mpro were identified. The mode of enzyme inhibition of these compounds was predicted by docking and molecular dynamic simulation. Compounds 1 (isolated as two conformers of S- and R-isomers), 2, and 4 were found to have promising in vitro inhibitory activity towards Mpro, with an IC50 values range of 0.36–0.89 µM comparable to the positive control GC376. The in silico investigation revealed compounds to achieve stable binding with the enzyme active site through multiple H-bonding and hydrophobic interactions. Additionally, the isolated compounds showed very good drug-likeness and ADMET properties. Our findings could be utilized in further in vitro and in vivo investigations to produce anti-SARS-CoV-2 drug candidates. These findings also provide critical structural information that could be used in the future for designing potent Mpro inhibitors.

Neoechinulin A as a Promising SARS-CoV-2 Mpro Inhibitor: In Vitro and In Silico Study Showing the Ability of Simulations in Discerning Active from Inactive Enzyme Inhibitors

“…The resulting top-ranked pose was almost identical to that of the co-crystallized one with an RMSD of 1.1 Å ( Figure S12 ). The generated binding poses were then visually investigated using Pymol software [ 13 , 39 ]. Step 2 (Δ G bind estimation step): Top-scoring poses resulted from the docking step were subjected to molecular dynamic simulations (MDS)-based binding free energy estimation (Δ G bind ) using the Free Energy Perturbation (FEP) method [ 40 ].…”

“…The resulting top-ranked pose was almost identical to that of the co-crystallized one with an RMSD of 1.1 Å ( Figure S12 ). The generated binding poses were then visually investigated using Pymol software [ 13 , 39 ].…”

“…Our group has reacted immediately with the pandemic, putting every effort to screen our available extracts, fractions, and pure compounds obtained from plants, endophytes, and microorganisms of marine and terrestrial origin for the discovery of antiviral hits against SARS-CoV-2 or its main protease (M pro ) as a potential target [ 13 , 14 , 15 , 16 , 17 , 18 ]. In the current study, we report the discovery of a previously reported indole diketopiperazine alkaloid neoechinulin A ( 1 ), as a promising SARS-CoV-2 M pro inhibitor through bioguided screening.…”

Isolation and Molecular Characterization of Indigenous Penicillium chrysogenum/rubens Strain Portfolio for Penicillin V Production

“…Moreover, P. chrysogenum clade produces secalonic acids D, F, and lumpidin-like compounds along with metabolites produced by P. rubens strains [ 4 ]. Penicillium strains are known for producing essential molecules, including enzymes, organic acids, terpenoids, and polyketides used in various industries ( Table 3 ) [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ].…”

Network Pharmacological Analysis of the Red Sea Sponge Hyrtios erectus Extract to Reveal Anticancer Efficacy of Corresponding Loaded Niosomes

“…The highly probable anticancer compounds predicted in the previous neural networking pharmacophore-based screening were subjected to an inverse docking-based virtual screening using the idTarget platform ( , accessed on 22 July 2022) [ 36 , 37 , 38 ]. The details of idTarget-based screening are discussed in the Supplementary Material and Methods .…”