Screening of the Roccustyrna Inhibitor for Spike
Protein-RBD-ACE2 Interaction.
In this study, we have shown that the QMMM designed Roccustyrna small
molecule which was designed in silico by using Topology Euclidean
Geometric and Artificial Intelligence-Driven Predictive Neural Networks
was engaged in the binding domains of the protein targets of of the
(pdb:1xak) (Figure 2/) with the docking energy values of the (T.Energy,
I.Energy, vdW, Coul, NumRotors, RMSD, Score), (-19.625, -35.483, 7.633,
-43.116, 7, -5.813) Kcal/mol, (Tables1,2) The Roccustyrna chemical
structure interacted into the binding sites of the protein targets of
(pdb:6w9c), (Figure 2/) with the negative docking energies of the
(T.Energy, I.Energy, vdW, Coul, NumRotors, RMSD, Score),
(-36.678,-55.648, -7.519, -48.129, 7, -6.762) Kcal/Mol. The same
combination of small molecules also generated hydrophobic interactions
when docked onto the binding cavities of the amino acid of the 168 PRO,
A1, 02J C with the docking energy values of the (-3.53, -2369, -1303,
-10.425, -3.42, -72.447, -13.394, -3.19, -70.551) Kcal/mol. Our new QMMM
designed cluster of quantum thinking small molecules additionally
involved in the generation of the hydrogen bonding within the PJE:C:5
(PJE-010) 010:C:6 Interacting chain (s) while generating hydrophobic
interactions when docked into the binding domains of the amino acid of
the 25THR, A6, 010 C domains with the docking energy values of the
(-3.73, - 2415, 179, - 7.156, -21.406, -66.898 -8.709, -22.779, -70.002)
Kcal/mol. The combination of GisitorviffirnaTM, Roccustyrna_gs1_TM,
and Roccustyrna_fr1_TM cluster of active pharmacophoric sites of the
2‐ ({[fluoro ({[ (2E) ‐5‐oxabicyclo [2.1.0]
pentan‐2‐ylidene] cyano‐lambda6‐sulfanyl}) methyl]phosphorylidene}
amino) ‐4,6‐dihydro‐1H‐purin‐6‐one (methylamino) ‐1,6‐ diazabicyclo
(3.2.0) heptan‐4‐yl) oxy} imino) interacted into the binding cavities
of the amino acid of the 26 THR, A6 010C with the docking energy values
of the (-3.81, -2415, -186, -7.156, -21.406, -66.898, -6.155, -24.392,
-64.757) Kcal/mol. The combination of GisitorviffirnaTM,
Roccustyrna_gs1_TM, and Roccustyrna_fr1_TM cluster of active
pharmacophoric sites of the 2‐ ({[fluoro ({[ (2E) ‐5‐oxabicyclo
[2.1.0] pentan‐2‐ylidene]cyano‐lambda6‐ sulfanyl})
methyl]phosphorylidene} amino) ‐4,6‐
dihydro‐1H‐purin‐6‐onedihydro‐3H‐purin‐9‐yl) ‐3‐ hydroxyoxolan generated
a docking effect which was involved in the generation of hydrogen bonds
when docked into the binding cavities of the amino acid of the 143 GLY A
6 010 C with the docking energy values of the (-1.93, -2.8, -145.29,
-1105, -2411, -8.911, -17.849, -65.703 -8.918, - 17.918,- 62.905)
Kcal/mol.
In addition, the CoMFA contour map of electrostatic regions around
Roccustyrna chemical structure indicated that the contact residues of
the Roccustyrna small molecule when docked onto the SARS-COV-2 protein
targets of (pdb:2zu5). (green, favored; yellow; disfavored) around the
Roccustyrna chemical structure hits the entire sequence of the amino
acid of the V-M-THR-25, V-S-THR-25, V-M-THR-26, V-S-HIS-41, V-M-LEU-141,
V-M-ASN-142, V-S-ASN-142, V-M-GLY-143, V-S-CYS-145, V-M-MET-165 with the
binding energy values of the -97.2 and -5.16512, -4.15949, - 9.8487,
-4.77062, -4.72901, -6.7295, -5.82428, - 5.35883, -4.2588, -5.37491
Kcal/mol respectively. (Figure 2/d) The same prototype pharmacophoric
elements named Roccustyrna when docked into the binding sites of the
amino acid of the 164HIS, A5, PJE C2. generated hydrogen interactions
with the binding energy values of the (-16 3.07, -153.73, -2408)
Kcal/mol/A, in the coupled atoms of the N3 and O2 with the docking
energy values of the (-12.282, -14.994, -67.123 - 15.161, 15.336,
68.144) Kcal.Mol. The binding patterns of the 02J:C:1 (02J) active sites
of the amino acid 168 PRO, A1, 02J C binding domains generated
hydrophobic interactions with docking energy values of the (-3.53,
-2369, - 1303, - 10.425, -3.42, -72.447, -13.394, -3.19, -70.551)
Kcal/mol/A inside the PJE:C:5 (PJE-010) + 010:C:6 interacting chain (s):
A C of the amino acid of the 164HIS, A5, PJE C2. (Figure 3/b).
D10-C-1099 DMS:A:402 (DMS) binding sites were also constructed when the
combined pharmacophoric elements of the combination of
GisitorviffirnaTM, Roccustyrna_gs1_TM, and Roccustyrna_fr1_TM
ligands docked inside the (pdb:6lu7) protein targets. Hydrogen Bonds
were then identified when the RoccustyrnaTM’s chemical coupled atoms
interacted within the 298 ARG A amino acid 402 DMS A Ng+ 2377 O2 binding
cavities with the docking energy values of the (-1.76, -2.73, -166.89,
-2331, 6.971, -0.756, -7.541 -9.700, -0.883, -7.581) Kcal/mol/A. Salt
Bridges were also shown to be involved in the generation of the
Sulfonium bonding when docked inside the DMS A 5.49 binding cavities of
the amino acid of the 295 ASP A domains with the docking energy values
of the (-402, -2376, -6.081, -1.005, -6.367 -10.436, -2.231, -5.560)
Kcal/mol/A. pi-Cation Interactions of sulfonium bonding within our small
molecule whole residue subsurface were also constructed within the 8 PHE
A amino acid 402 DMS A pharmacophoric sites with the docking energy
values of the (-4.70, -1.01, -2376, -6.081,-1.005, -6.367, -8.339,
-4.556, -4.264) Kcal/mo/A. (Figure 3/d). Hydrophobic Interactions were
simultaneously generated by the Roccustyrna chemical residues when
docked in the (pdb:6lu7) protein targets of inside the D10-H-1099.
X77:A:401 (X77) side domains within the active sites of the amino acids
of the 41 HIS A 401 X77 A, 165 MET A 401 X77 A, and 166 GLU A 401 X77 A
with the docking energy values of the (-3.75, -4670, -609, -20.444,
-13.613, -29.034, -19.778, -13.574, -32.721 -3.90, -4673, -2529,
-19.389, -17.775, -28.688, -16.611, 16.152, -26.489, -3.86, -4661,
-2546, -17.350, -23.138, -25.438 -16.439, -20.244, -23.055, -189 GLN A
401 X77 A -3.90, -4657,- 2881, -21.763, -15.894, -23.429 -24.934,
-13.635, -23.312) Kcal/mol/A showing that my AI-quantum thinking
chemical structure named Roccustyrna is capable of generating Hydrogen
Bonds when docked onto the 41 HIS A 401 X77 A, 143 GLY A 401 X77 A, 144
SER A 401 X77 A, and 166 GLU A 401 X77 A, sequence of amino acids while
targeting the Npl 4680 N2, O3 4679 N2 Nam 4682 O2, and Nam 4683 O2
binding sites with the binding free energy values of the (-3.46, -3.79,
-106.13, -611, - 20.860, -19.573, - 32.52, -19.394, -16.086, -32.767,
-2.17, -2.94, -148.03, -2216 -19.635, -22.244, -29.036 -18.779, -24.455,
-30.773, -3.14, -3.42, -101.78, -2228 -16.096, -21.679, -26.816,
-14.503, -23.707, -29.056, -1.98, -2.80, -158.32, -2542 - 18.546,
-18.654, -26.028 -16.172,- 18.348, -24.583) Kcal/molA respectively.
(Figure 3/f). The2‐ ({[fluoro ({[ (2E) ‐5‐oxabicyclo [2.1.0]
pentan‐2‐ylidene] cyano‐lambda6‐sulfanyl}) methyl]
phosphorylidene} amino) ‐4,6‐dihydro‐1H‐purin‐6‐one (1Z) ‐2‐{
((2S,3S,5R) ‐5‐ (2‐amino‐ 6‐oxo‐6,9‐ dihydro ‐1H‐purin‐9‐yl) ‐
3‐hydroxyoxolan‐2‐yl) methylidene} ‐2‐cyano‐ 1‐ ({ ((2S,4R,5R) ‐2‐
methyl‐2‐ (methylamino) ‐1,6‐diazabicyclo (3.2.0) heptan‐4‐yl) oxy}
imino) ‐1lambda5,2lambda5‐azap hosphiridin‐1‐ylium. druggable scaffold
of the Roccustyrna small molecule therefore competes with endogenous
SARS-CoV2 PLpro for binding to Lys711 and Arg355 targeting into the
binding domains of the critical SARS-CoV2 PLpro residues onto the SARS-
COV-2 protein targets of (pdb:2zu5) within the binding sites of the
amino acid of the V-M-THR-25, V-S-THR-25, V-M-THR-26, V-S-HIS-41,
V-M-LEU-141, V-M-ASN- 142, V-S-ASN-142, V-M-GLY-143, V-S-CYS-145,
V-M-MET-165 with the binding energy values of the -97.2 and -5.16512,
-4.15949, -9.8487, -4.77062, -4.72901, -6.7295, - 5.82428, -5.35883,
-4.2588, -5.37491 respectively
CoMFA contour map analysis of electrostatic regions around the
Roccustyrna small molecule a chemical structure indicated to us that
Hydrogen bonds, Salt bridges and Metal complexes containing Diphosphate,
dihydrogen and ION binding sites were generated into the contact
residues of the Roccustyrna’s small molecule when docked onto the SARS-
COV-2 protein targets of the (pdb:2zu5) within the sequence of the amino
acid of the V-M-THR-25, V-S-THR-25, V-M-THR-26, V-S-HIS-41, V-M-LEU-141,
V-M-ASN-142, V-S-ASN-142, V-M-GLY-143, V-S-CYS-145, V-M-MET-165 with the
binding energy values of the negative docking values of the (-97.2 and -
5.16512, -4.15949, -9.8487, - 4.77062, -4.72901, -6.7295, -5.82428,
-5.35883, -4.2588, -5.37491) Kcal/mol/A respectively. (Figure 4/a),
(Table 4/), (Table 5/) The Roccustyrna DMS:A:402 (DMS) binding sites
into the 524 Nam 2578 O2 02J (5-Methylisoxazole-3-carboxylic acid)
domains inside the 65 ASN A 402 DMS A cavities of the pdb:6LU7 protein
targets of generated Hydrogen Bonds of the docking energy values of the
(-2.05, -2.94, -148.0, -8.211, -20.857, -29.787 -11.058, -20.242,
-30.160 298)) Kcal/mol/A. Salt Bridges were also constructed when our
prototype’s surface sites docked inside the DMS -A, Ng+ 2582 O2 binding
pocket cavities of the amino acid of the ARG A 403 with the docking
energy values of the (-1.93, -2.87, -160.38, -2512 -7.044, -0.753,
-7.469 9.865, -1.270, -7.327) Kcal/mol/A. Sulfonium bonding were also
constructed when our small molecule 403 DMS A contact residues of the
binding sites of the 295 ASP amino acid with the docking energy values
of the (-5.31, -2581, -6.227, -1.042, -6.293 -10.460,- 2.019, -5.344)
Kcal/mol/A. (Figure 4/b). 999 ZN D 20947 Zn, ZN:A:998 (ZN) and 998 ZN A
20940 Zn 470 S Metal Complexes were constructed into the 02J
(5-Methylisoxazole-3-carboxylic acid) PJE-C-56LU7 Roccustyrna’s (1Z)
‐2‐{((2S,3S,5R) ‐5‐ (2‐amino‐6‐oxo‐6,9‐dihydro‐1H‐purin‐9‐yl ‐4‐yl)
oxy} imino) ‐ 1lambda5,2lambda5‐azaphosphiridin‐1‐ylium. binding sites
inside the 117 CYS D, 74 CYS A amino acids tetrahedral side chains with
the docking energy values of the (-1103.746, -101.848, -13.968, -
103.306,- 102.613, -16.001 -1118.874, -104.964,- 32.313 -118.938,
-103.573, -30.6090Kcal/mol/A generated indicating that our
multi-targeted drug design could of generating a self-assembled
monolayer inside the 1: Mg, NA (1), 1, 10P, G Metal Complexes when
docked onto the 1,553A binding cavities of the amino acid of the ARG
into the pdb:7bv2 protein targets. The combination of GisitorviffirnaTM,
Roccustyrna_gs1_TM, and Roccustyrna_fr1_TM clusterpharmacophoric
(1Z) ‐2‐{ ((2S,3S,5R) ‐ 5‐ (2‐amino‐6‐2‐yl) methylidene}
‐2‐cyano‐12‐({[fluoro({[(2E) ‐5‐oxabicyclo [2.1.0]
pentan‐2‐ylidene] cyano‐lambda6‐sulfanyl}) methyl]phosphorylidene}
amino) ‐4,6‐dihydro‐1H‐purin‐6‐one‐ ({ ((2S,4R,5R) ‐2‐methyl‐2‐
(methylamino) ‐1,6‐dia-zabicyclo (3.2.0) heptan‐4‐yl) oxy} imino)
‐1lambda5,2lambda5‐ azaphosphiridin‐1‐ylium. active site of the
2-lambda5‐azaphosphiridin‐1‐ylium was engaged in hydrogen bonding
interactions with the formation of hydrogen bonds inside the N3 1266 O2
binding cavities of the amino acid of the 143 GLY, A6, 010 C with the
docking energy values of the (-1.93, -2.80, -145.29, -1105, -3.81,
-2415, -186, -7.156, -21.406, -66.898 -6.155, -24.392, -64.757, -2411,
-8.911, -17.849, -65.703 -8.918, -17.918, -62.905, -2.16, -3.07,
-153.73, -2408, -12.282, -14.994, -67.123, -15.161, -15.336, -68.144)
Kcal/mol. The Roccustyrna small molecule involved also in the generation
of the hydrophobic interactions within the binding domains of the amino
acid of the 25 THR A 6 010 C with the docking energy values of the 3.73,
2415, 179, -7.156, 21.406, 66.898 -8.709, 22.779, 70.002Kcal/mol as
illustrated in the (Figure 4/c). (Table 4/), (Figure 4/d). In this drug
designing project the electrostatic regions around the combination of
GisitorviffirnaTM, Roccustyrna_gs1_TM, and Roccu- styrna_fr1_TM
pharmacophoric elements of (7aR) ‐5‐amino‐N‐[(S) ‐{2‐[(S) ‐[(E) ‐
(aminomethylidene) amino](cyano) methyl]hydrazin‐1‐ yl}
(aziridin‐1‐yl) phosphoryl]‐1‐[(2E) ‐2‐[(fluoromethanimidoyl)
imino]acetyl]‐7‐oxo‐1H,7H,7aH‐pyrazolo[4,3‐d]pyrimidine‐3‐carboxamide;
N‐{[(2‐amino‐6‐oxo‐6,9‐dihydro‐1H‐purin‐9‐yl)
amino]({1‐[5‐({[cyano({1‐[(diaminomethylidene)
amino]ethenyl}) amino]oxy} methyl)
‐3,4‐dihydroxyoxolan‐2‐yl]‐1H‐1,2,4‐triazol‐3‐yl} formamido)
phosphoryl} ‐6‐fluoro‐3,4‐dihydropyrazine‐2‐carboxamide;
[3‐(2‐amino‐5‐sulfanylidene‐1,2,4‐triazolidin‐3‐yl)
oxaziridin‐2‐yl]({3‐sulfanylidene‐1,2,4,6‐tetraazabicyclo
[3.1.0]hexan‐6‐yl}) phosphoroso1‐(3,4,5‐trifluorooxolan‐2‐yl)
‐1H‐1,2,4‐triazole‐3‐carboxylate 3‐hydroxyoxolan‐2‐yl) methylidene} ‐2‐
cyano‐1‐ ({ ((2S,4R,5R) ‐2‐methyl‐2‐ (methylamino) ‐1,6‐diazabicyclo
(3.2.0) heptan‐4‐yl) oxy} imino) ‐1lambda5,2- lambda5‐ azaphosphiridin
‐1‐ylium. substrate targets the SARS-COV-2 protein targets of (pdb:7bv2)
with the docking values if the (Total Docking Energy = -1.004,
vdW=-6.072, Coulomb = -7.135, Internal = 12.203) Kcal/mol/A, (Figure
4/a), (Figure 4/f) showing that combination of GisitorviffirnaTM,
Roccustyrna_gs1_TM, and Roccustyrna_fr1_TM binding site (s) inside
the (pdb:6lu7) binding domains of the 02J:C:1 (02J) regions while
co-generating Hydrophobic Interactions and Hydrogen Bonds against the
coupled atoms of the Nam 2411 O3 inside the cavities of the crucial
entering amino acids of the 25 THR A 6 010 C and 143 GLY A 6 010 C with
the docking energy values of the (-3.73, -2415, -179, -7.156, 21.406,
-66.898, -8.709, -22.779, -70.002, -26, -81, -2415, -186, -7.156,
-21.406, -66.898, -6.155, -24.392,- 64.757,- 1.93, -2.80, -145,.-29,
-1105, -8.911, 17.849, -65.703, -8.918,-17.918,-62.905.) Kcal/mol/A
respectively. In this project, we implemented Quantum Heuristic
Fragmentation Algorithms for the merging and recoring of the hit
selected Drug Pair interactions by using Quantum Hamiltonians for the
=γB⋅ (Sˆ1+Sˆ2) +Iˆ⋅A⋅Sˆ2 (equation52), Sˆi= (σx,σy,σz) Iˆρs (t) = TrI (U
(t) ρ (0) U† (t)) (equation52) ,ρI (0) =I/2P (t′) =d M (t′) (equation53)
M=f (t′) dt′, (equation54) ρ¯s=∫−∞0f (t′) ρs (t′) (equation55) dt′=∫0∞f
(t) ρs (t) dt,∫−∞0f (t′) (equation56) dt=∫0f(t)
dt=1ρ¯sρ¯sρ¯sρ¯(equation57) s(,π/2) ρ¯sρs(0) ρ¯s (equation58)
,QFI≈∑i=01Re (ρi12) 2 (1ρi11+1ρi22) + (ρi11−ρi22) 2 ρi11+ρi22
(equation59) ,ρ1ij=〈φi 〈1 ρs (0) φj〉1〉ρ (equation60) 0ij=〈φi 〈0 ρs
(0) φj〉 0〉 0〉 1〉 (equation23-55) H1=γB0⋅Sˆ1 Re (ρi12) ρi12ρs (0) ρ¯s
(equation21-45) S〉=12 (〉−01〉) 30%ρs (equation59) ρ¯s=H⊗m
0〉⊗m=H⊗H⊗⋯⊗H 00⋯0=12 (0+ 1) ⊗12 (0+ 1) ⊗⋯⊗12 (0+) =12m (00⋯0〉+00⋯1〉)
+⋯+ (11⋯1) equation (60). (Figure 2/a) Electrostatic CoMFA analysis of
the contact residues of the best docking poses of the contact merged
chemical residues of the entire Roccustyrna chemical structure when
docked onto the SARS-COV-2 protein targets of (pdb:3fqq) hits the
positively charged groups and red regions favored by negatively charged
groups within the sequence of the binding domain of the amino acid of
the V-S-HIS-159, V-S-ARG-16, V-S-ARG-112, V-M-GLU-148, V-M-PHE-15,
V-S-PHE-15, V-S-HIS-159, V-M-TYR-161 with the docking energy values of
the (-101, - 14.0762, -5.11094, -7.98447, -4.17314, -4.43549, -9.66939,
-9.42926, -7.30085) Kcal/mol/A. (Figure 2/b) Other QSAR/CoMFA contour
map experiments of electrostatic regions of the binding interaction of
the entire pharmacophoric residues of the Roccustyrna chemical design
when docked onto the SARS-COV-2 protein binding sites of the
electrostatic surface view of active site pocket of its active contact
residues of the Roccustyrna small molecule when docked onto the
SARS-COV-2 protein targets of (pdb:6xs6), interacted negatively with all
the charged groups of the sequence of the amino acid of the V-M-LYS-557,
V-S-LYS-557, V-M-ARG-567, V-M-ASP-568, V-S-ASP-574, V-S-PHE-43,
V-M-ARG-44, V-M-SER-45, V-S-SER-45 with the docking energy values of the
-85.8, and (-5.56004, -5.0011, -8.38956, - 5.77168, -6.13664, - 12.8661,
-5.37546, -6.10391, -5.00928) Kcal/mol respectively. (Figure 2/c)
Moreover, Cluster of the QSAR/QMMM/CoMFA map analysis of electrostatic
regions around the contact residues of the Roccustyrna small molecule
when docked onto the SARS-COV-2 protein targets of (pdb:2ghv). (green,
favored; yellow; disfavored) around the entire Roccustyrna chemical
structure regions has shown that our innovative drug design generated
negatively charged groups within the sequence of the amino acid of the
H-M-ASN-33, H-S-ASN-33, H-S-TYR-356, H-M-ASN-424, V-M-ASN-33,
V-M-ALA-331, V-M-THR-332, V-S-THR-332, V-S-TYR-356, V-S-TRP-423,
V-S-ILE-428, V-S-ARG-495 with the docking energy values of the -104.7
and-3.45708, -3.5, - 3.97711, -3.5, -5.33228, -6.79753, -7.9376, -
6.69969, -12.2528, -7.66989, -8.15072, -7.00332Kcal/mol respectively.
The Roccustyrna small molecule hits also the entire binding domains of
the SARS-COV-2 protein targets of (pdb:6w9c) within the sequence of the
amino acid of the V-S-PRO-59, V-S-ARG-65, V-M-THR-75, V-S-THR-75,
V-M-PRO-77, V-S-PRO-77, V-M-HIS-47, V-S-HIS-47 with the docking energies
of the -83.9, -4.21999, -12.6164, -7.60372, -6.69528, -5.89416, -
6.40663, - 5.51621, -7.99273. (Figure 2/e) As illustrated in the (Figure
3/) the Roccustyrna small molecule generated also negative docking
energy values with a potential inhibitory effect when docked against the
sequence of the amino acids of the protein targets of (PDB: 6YI3) of the
N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid
phosphoprotein which is essential for linking the viral genome to the
viral membrane. (Figure 4/d), (Figure 4/e) In this project for the first
time we generated a Comparative Docking Cluster Analysis between the
Remdesivir and our prototype Roccustyrnasmall molecule when docked onto
the SARS-COV-2 protein targets of (pdb:7bv2), with the docking energy
values of the (Num_Members = 40, Total_Energy = 2.103, vdW = -5.122,
Coulomb = - 4.977, Internal = 12.203, rmsd = 3.183 and $Number of
Clusters = 10, $Seed = -1985, $Leader_Info 1 { Num_Members = 63
Total_Energy = -0.883, vdW = -6.041, Coulomb = -7.045, Internal =
12.203, rmsd = 0.000) respectively. (Figure 3/). A quantum distribution
correlation similarity analysis was implemented regarding the
Roccustyrna active fragments of the: 20107.0352225 (NH+)
#CN=C1C=NC=N12182. 03997355 (NH2+) =C1C=NC=
(Figure 4/f), (Figure 4/g), (Figure 4/h) Finally, the Roccustyrna
chemical structure generated an inhibitory docking effect of high
negative binding energy docking values of the -66,7 Kcal/mol when docked
onto the cav7bv2_POP binding domains within the amino acids of the
V-M-LYS-551, V-S-LYS-551, V-S-ARG-553, V-S-ASP-618, V-M-TYR-619,
V-M-PRO-620 with the docking energy values of the (-4.71516, -10.4842,
-4.7999, - 6.65538, - 5.1339,-6.28532) Kcal/mol. (Figure 5/a), (Figure
5/b), (Figure 5/c), (Figure 6/) On the other hand the Remdesivir drug
when combined to the Roccustyrna small molecule interacted at the same
binding domains of the amino acids of the V-M-LYS-551, V-S-LYS-551,
V-S-ARG-553, V-S-ASP-618, V-M-TYR-619, V-M-PRO-620 with positive and
zero docking values of the +42.1, -0.104885, -0.19986, +25.0575,
Kcal/mol. That means that the Remdesivir drug could induce the COVID19
disease.