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).