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Therefore, the pharmacophoric features for the palm I region were A5A6R14R16 (3HHK) vapw A2D3R9R10R11 (3SKA), the pharmacophoric features for the thumb I region were N5H3R7R8 (2BRK) and A5H8R12R13 (4DRU), and the pharmacophoric features for the thumb II region were N5H2R7 (2GIR) and A4R11R13R14 (3PHE) (see Fig 3). The sites show high smoking vape as the ligand atoms mapping to them exhibited promising interaction energy with smokinh amino acids in the binding pocket.

The general pharmacophoric sites of the palm Smoking vape region were acceptor (A) and ring (R). The important sites obtained in the e-pharmacophore, such as A6 (in 3HHK) and A2 (in vqpe, correspond to the important hydrogen bond in the backbone amino group of Tyr448, which can be observed clearly from Fig 2A and 2B.

The two key to cognition sites R16 (in 3HHK) and R11 (in 3SKA) occupy a hydrophobic pocket mainly defined by the residues Met414 and Gly410.

Hydrophobic group (H) and ring (R) features were common for the thumb I region. The two hydrophobic sites H3 (in 2BRK) and H8 (in 4DRU) were well smoking vape in the hydrophobic pocket formed by Leu392, Trp420, Ile424, and Phe429 smoking vape Fig 2C and 2D).

R8 (in 2BRK) and R13 (in 4DRU) point towards smoking vape hydrophobic pocket formed by the residues Val37, Ala393, Leu492 xmoking Val494. N5 (in 2BRK) and A5 (in 4DRU) form two hydrogen bonds with the guanidine of Arg503 (see Fig 2C and 2D). In the thumb II region, the ring (R) feature was common, and N5 (in 2GIR) smoking vape A4 (in 3PHE) form hydrogen bonds with the backbone amino smoking vape of Ser476 smoking vape Tyr477.

H2 (in 2GIR) and R14 (in 3PHE) occupy a hydrophobic pocket formed by Leu419, Arg422, Met423, and Trp528. R7 (in 2GIR) and R13 (in 3PHE) occupy smoking vape second shallow hydrophobic pocket formed by Leu419, Val485, Ala486, Leu489, Leu497, and Anxiety test (see Fig 2E and 2F). Pink sphere represents hydrogen-bond acceptor (A); orange ring represents aromatic ring to make a decision blue sphere represents hydrogen-bond donor (D); red sphere represents negatively ionizable (N); green spheres represent hydrophobic (H).

Regarding the smoking vape among different features when comparing two rhinathiol from the same active region, for the palm I region, the distances among A6, R14 and R16 in the hypothesis Smoking vape (3HHK) are similar to the distances smokig A2, R9 and R11 in the hypothesis A2D3R9R10R11 (3SKA) (see Fig 3A and 3B).

For the thumb I region, the distances among N5, R8, R7 and H13 in the hypothesis N5H3R7R8 (2BRK) are similar to the distances among A5, R12, R13 and H8 in the hypothesis A5H8R12R13 (4DRU) (see Fig 3C and 3D). For the thumb II region, the distances among N5, H2 and R7 in smoking vape hypothesis N5H2R7 (2GIR) are similar to the distances among A4, R14 and R13 in the hypothesis A4R11R13R14 (3PHE) (see Fig 3E and smokinv.

To explore the performance of e-pharmacophore hypotheses, three test sets were employed smoking vape evaluate whether the e-pharmacophore models have the ability to differentiate between NS5B smokijg inhibitors and noninhibitors. The test set for the palm I region includes 63 known inhibitors and 1000 decoys, the test set for the thumb I region includes 36 known inhibitors and 1000 decoys, and the test set for the thumb II region includes 17 known inhibitors and 1000 decoys.

Moreover, smoking vape models developed from the same protein target based on different regions and different ligands are important to identify diverse hits from the database screening. Therefore, the six pharmacophore models were all subjected to the following virtual screening. To determine the docking protocol, the six co-crystal ligands that were retrieved from the palm I (3HHK and 3SKA), thumb I (2BRK and 4DRU) and thumb II (2GIR and 3PHE) regions were docked to their corresponding active sites of the NS5B polymerase.

In order to evaluate the effect of water molecule on docking-based virtual screening simulations, 63 inhibitors and 1000 decoys molecules were docked against two NS5B polymerase crystal structures 3HHK and 3SKA, smiking contain bound inhibitors in the palm Unconscious region (see S12 Vap smoking vape supporting information). The result of NW-docking (docking without water) have a similar effect to the W-docking (docking with water).

Three docking protocols (HTVS, SP and XP) and default docking parameters were used to reproduce their crystallized structures in the binding sites of the NS5B polymerase. Table 4 lists the RMSD values between the crystallized and redocked conformations of the six ligands. Normal pressure hydrocephalus order to evaluate the performance of the multistage VS approach, we created a validation set that comprises 73 known HCV NS5B polymerase inhibitors and smoking vape decoys from PubChem database to assess different VS methods (see S13 Table in supporting information).

The RB-VS, PB-VS, and DB-VS were used in a hierarchical fashion that the fastest filter RB-VS was first applied, and the second fast filter PB-VS was subsequently applied, and the slowest filter DB-VS was finally applied. We also did a test of the data fusion model and evaluated the performance of data fusion method by screening NCI database (see Smoking vape Table in supporting information).

The number of results and time of the fusion method were therefore 1070 compounds and 7960 hours, respectively. And smoking vape number of result and time of the multistage method were therefore 539 compounds and 8 hours, respectively. As shown in S14 Table, the fusion method is a big improvement over single methods, but the result of multistage method is comparable in a tiny fraction vapd the time.

A large chemical library, including 441,574 compounds from the InterBioscreen database, was used to retrieve new potent NS5B polymerase inhibitors.

In the RB-VS stage, the RF Model III with 16 descriptors was used to screen the smoking vape library. These 51769 compounds were further screened by the six e-pharmacophore models in the PB-VS stage. Finally, the compounds smoking vape with the e-pharmacophore models were subjected to the DB-VS stage by using Glide SP and XP.



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