Identification of Influenza PAN Endonuclease Inhibitors via 3D-QSAR Modeling and Docking-Based Virtual Screening

Abstract

Structural and biochemical studies elucidate that PAN may contribute to the host protein shutdown observed during influenza A infection. Thus, inhibition of the endonuclease activity of viral RdRP is an attractive approach for novel antiviral therapy. In order to envisage structurally diverse novel compounds with better efficacy as PAN endonuclease inhibitors, a ligand-based-pharmacophore model was developed using 3D-QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery Studio. As the training set, 25 compounds were taken to generate a significant pharmacophore model. The selected pharmacophore Hypo1 was further validated by 12 compounds in the test set and was used as a query model for further screening of 1916 compounds containing 71 HIV-1 integrase inhibitors, 37 antibacterial inhibitors, 131 antiviral inhibitors and other 1677 approved drugs by the FDA. Then, six compounds (Hit01–Hit06) with estimated activity values less than 10 μM were subjected to ADMET study and toxicity assessment. Only one potential inhibitory ‘hit’ molecule (Hit01, raltegravir’s derivative) was further scrutinized by molecular docking analysis on the active site of PAN endonuclease (PDB ID: 6E6W). Hit01 was utilized for designing novel potential PAN endonuclease inhibitors through lead optimization, and then compounds were screened by pharmacophore Hypo1 and docking studies. Six raltegravir’s derivatives with significant estimated activity values and docking scores were obtained. Further, these results certainly do not confirm or indicate the seven compounds (Hit01, Hit07, Hit08, Hit09, Hit10, Hit11 and Hit12) have antiviral activity, and extensive wet-laboratory experimentation is needed to transmute these compounds into clinical drugs.

Integrated Virtual Screening and Validation toward Potential HPPD Inhibition Herbicide

“…The result of cost analysis was that all Hypogen models presented a total cost value between fixed cost and null cost, and their ΔCost values were greater than 60 bits. Especially, Hypogen 01 possessed the highest ΔCost value and the closest total cost value to the fixed cost, which indicated that Hypogen 01 had the best statistical significance …”

Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors

“…This provides a triad of oxygen donor atoms (including oxygen donor atoms from the ketone and carboxylic acid groups), creating a 5-membered chelate ring at Mn 1 and a 6-membered chelate ring at Mn 2 . Compounds 1 and 2 also displayed hydrogen bonding between the ketone donor from the hydroxypyridinone ring and Lys134 …”

“…Compounds 1 and 2 also displayed hydrogen bonding between the ketone donor from the hydroxypyridinone ring and Lys134. 32 Previous crystallographic studies have focused on compounds containing a triad of chelating oxygen atoms that bind in a tridentate fashion, displacing three of the coordinating water molecules. 21,22 Compounds 1, 2, 3, and 5 present the same triad and display similar binding poses, coordinating Mn 1 through the ketone and Mn 2 through the carboxylate, with the hydroxyl group bridging Mn 1 and Mn 2 (Figure 2).…”

“…Compounds 1 and 2 also displayed hydrogen bonding between the ketone donor from the hydroxypyridinone ring and Lys134. 32 …”

Antihypertensive Effect, ACE Inhibitory Activity, and Stability of Umami Peptides from Yeast Extract

“…At present, the practical utilization of pharmacophore models and molecular docking underpin virtual screening and the exploration mechanism of active compounds. For example, these methods have been used in designing inhibitors for polymerase acidic protein endonuclease and topoisomerase I . Application of the pharmacophore model is a cost-efficient approach for discovering novel ACE inhibitory peptides, but substantiating their antihypertensive effects in vivo and in vitro remains essential.…”