Screening NuBEE Phyto-library and COVID2019 targets.
Virtual screening of the final proposed model and high throughput molecular docking based on existing literature were implemented to a collection of 9591 drugs including 2037 chemical structures of FDA-approved small molecule drugs and (2,3-14,17) over 6000 herbals and physical extracts from the NuBBEDB updated database to get an insight into the potential inhibitors and to uncover chemical and biological druggable information from Brazilian biodiversity (4-6,17). Drugs selected for the docking studies with an ideal number of non-hydrogen and metal atoms not related with macromolecules, organic and inorganic active fragments (e.g, Pt, Fe, Hg, etc.) below 5 or above 10, physical elements and drugs having Molecular Weight > 120, and already approved drugs that are consisted of original pharmacophoric elements of approved drugs into specific subcategories of the prototropic tautomer, separate enantiomer, and protomer fingerprint alternatives. (7,8,17,18) Parallel Virtual screening technique for molecular docking was deployed at the center of the X: 228.75, Y:190.82, and Z: 304.15. on its .pdbqt converted libraries of small molecules for the motif binding target sites using standard Web technologies such as CSS, HTML, and JavaScript (AJAX) including graphics, text-based, and spectral files. (9,13-17) When more than one form of the screened drugs and physical elements for the cross-validation (e.g, more than one protomer, more than one enantiomer, etc.) were screened, as suitable druggable candidates for re-coring and fragmenting the forms with the highest GP and Docking Energy values were considered in the ranking. (14,16,17) Finally, drugs and selected NuBBEDB physical extracts were docked according to the descending GP docking and binding energy values and only the screened hit candidates generating the highest binding energy values were considered for fragmenting and re-merging into the Roccustyrna small molecule using the BiogenetligandorolTM cluster
The whole set of molecules able to interact with the SARS-CoV PLpro enzyme were extracted after extensive machine learning similarity studies, retrieving only those small-molecule ligands with absolute IC50 values. (2-17,34) This druggable .sdf set consisted of 11 PLpro approved inhibitors. Depending on the cross-docking energy activities and fitness scoring analysis threshold, out of 11 compounds, 300 small molecule compounds with proven anti-viral properties were characterized as Actives and 153 molecules were categorized as Inactives. Physarum-prize-collective for molecular docking algorithm, Schrodinger-inspired Neural Matrix Factorization, and a drug repositioning scoring analysis were implemented to a hybrid collection of the Natural Products of the Chemistry Institute of UNESP, Araraquara/SP, and NuBBEDB physical extracts (9-17,35). (10-17,36) Protein-molecule complexes, (4,5,7,8-17) followed by structural relaxation were generated through (8,13-117) flexible-ligand rigid-receptor molecular docking (7,9,13,16-17) in these local energy minimization to optimize protein-ligand interactions capping the C- and N-terminal for each active druggable fragment with i-GEMDOCK (3-14,17) through cycles in all keeping conserved amino-acids within 4 Å of all the docked ligands of each cation arrangement as consideration for each relaxed chemical structure free of local energy and geometry minimizations. (1,2,5-17,34,35) Virtual screening experiments generated with KNIME pipelined DockThor Virtual Screening tool for the NuBBEDB and e-Drug3D dataset and for the ChEMBL database, at the reference pH (6.6 to 7.4) for all SARS-CoV-2 drug targets including the contig maps (a set of overlapping DNA segments) as were assembled with the use of CLC Genomics software, version 4.6.1 (CLC Bio) publicly and are available so far. (BetaCoV/Wuhan/IVDC-HB-01/2020|EPI_ISL_402119), (e.g, N-terminal S1 subunit, PLpro, NendoU, (residue 14–685) in Spike Mpro, RdRp, and complete genome sequences of the three novel coronaviruses were submitted to GISAID (BetaCoV/Wuhan/IVDC-HB-01/2019, accession ID: EPI_ISL_402119; BetaCoV/Wuhan/IVDC-HB-04/2020, accession ID: EPI_ISL_402120_BetaCoV/Wuhan/IVDC-HB-05/2019, accession ID: EPI_ISL_402121) and a C-terminal S2 region N protein) were prepared for GEMDOCK docking experiments using the wild isogenic type of the transcriptomic variants and 10 best matching physical and chemical small molecule compounds (Table 1/) after exhaustive virtual screening analysis was obtained accordingly, Colchicine, Raltegravir, Hexacosanol, Benzoxazolinon, Carboxy-Pentaric acid, Ursane, Antheraxanthin, RA-XIII, Crotonate and Byrsonima Coccolobifolia against the SARS-COV-2 protein targets of the (pdb:1xak), (pdb:6xs6) and (pdb:6lu7). (6,7-17,36) For each target, all crucial amino-acids involved virtually in this project of the cut-out parallel docking system when linked together with hydrogens were then collected and the hit candidates who energetically favored within 8 Å of any docked molecule onto the hydrophobic side chain were then used to build a reduced phase docking system to be in contact with water where the [P@@](=O) (NC(=O) c 1nc(F) cnc1) (NC(=O) c1nn(c2o c(c(O) c2O) CON(C(=[N]=C(N) N) C) CN) cn1) Nn1c2nc([nH ]c(=O) c2nc1) N.C\1(=C/2\ON2[P@](=O) (N2N3N[C](=N[C@H]23) =S) OC(=O) c2nn(c3oc(c(F) c3F) F) cn2) /N(N) N=[C](=S) N1.[P@@](=O) (N1CC1) (NC(=O) c1nn(c2c1[nH]c(nc2=O) N) C(=O) /C=N/C(=N) F) N/N=C(/N=C/N) \CN [P@] (=O) (O[P@@] (=O) (O) NC (=O) CC[C@H] (N) C (=O) N[C@H] (C (=O) N[C@H](C (=O) O) CCSC) CCC(=O) N) (O) OC1=N[C@H]2N=CN=C2C(=O) N1[P@@](=O(NC( =O) c1nc (F) cnc1(NC(=O) c1nn(c2oc(c(O) c2O) CON(C([N]=C(N) N) C) CN) cn1) Nn1c2nc([nH]c(=O) c2nc1) N. C\1(=C/2\ON2[P@] (=O) (N2N3N[C (=N[C@H]23) =S ) OC(=O) c2nn(c3oc(c(F) c3F) F) cn2) /N(N) N=[C](=S) N1.[P@@ ](=O) (N1CC1) (NC(=O ) c1nn(c2c1[n H]c(nc2=O) N) C( =O ) /C=N/C(=N) F) N/N= C(/N=C/N) \CN subscript. In the first smiles term in the spaces of targeted sequences referred to the difference of the free energy calculated using the protein-ligand (PL), protein (P), and ligand (L) sequence of amino acid conformations bonded evaluations for dispersion/repulsion, hydrogen bonding, electrostatics, and desolvation to the central atom of each screened compound. (10,17,37) (Figure 1///). The GQM (X) refers to the energy of the cluster of the physical small molecule known as the R group from the docked complex, in the free unbound state the fourth term corresponds to the change in conformational entropy, which were generated and the second and third unbound states of ligand side-chain conformations are calculated through local energy minimization as ∆GQMconf (X) = GQMo (X) − GQM (X), (X = L, P) (equation1) where GQMo (X) is the energy of the isolated active fragments in the conformation of the docked PL on both protein and molecule complex Inhibitors and conformations when applied Bioactivity-guided Fractionations for the cluster of the selected compounds of the Colchicine, Raltegravir, Hexacosanol, Benzoxazolinon, Carboxy-Pentaric acid, Ursane, Antheraxanthin, RA-XIII, Crotonate and Byrsonima coccolobifolia Leaves and Stems to be fragmented, re-cored and accordingly merged into the combination of GisitorviffirnaTM, Roccustyrna_gs1_TM, and Roccustyrna_fr1_TM small hyperactive druggable scaffolds (3,4,17,36). The acknowledgment of the binding of the selected 8 physical compounds to their full-genome evolutionary novel coronavirus (2019-nCoV) protein targets was accomplished using Molinspiration (http://www.molinspiration.com/cgi-bin/properties) and DrugBank (1,11,12,13,15,17,34).