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.