In this computational drug design project we provided an extensive combination of toolboxes by applying black-hole solution to Einstein’s Eqs for perfor ming quantum communication, neural matrix factorizations, cryptography, Schrödinger inspired docking algorithms, and other Information-theoretic tasks in MathCast programming language, and compared these algorithms by means of mean percentile free energy ranking, in a new recall-based evaluation metric for the Insilco design of a Novel Series of RoccuffirnaTMQMMMCoRoNNARRFr anti- (nCoV-19) annotated ligands. (Figure S1a). 3D Docking interactions of the selected NuBEE physical elements inside the PDB:6XS6, SARS-CoV-2 Spike D614G variant were combined to various general docking results including heuristic horizon topologies, into near-horizon pharmacophoric fragmentations as applied to Euclidean symmetries ranging from applied supergravity theories to a system of intrinsically positioned cables. (35, 36, 37, 38, 39) (Table S1). Docking energy rankings of the physical hit compoundsof Wyerone, bis- (5-for mylfurfuryl) ether, Monocrotaline, and Zeatin (Figure S1f), Methoxsalen, behenic acid, Bergapten, L-gamma -Glutamyl-S-allylthio-L-cysteine, Oleic Acid, Sursane, Hesperetin, Adenosine, and Eriodictyol (Figure S1g), Baicalein-7-methyl ether, Euglobal III, and the Linoleic Acid residues (Figure S1h), Atrazine, Genistein, Pregnenolone ligands (Figure S1i) when docked onto the SARS-COV-2 protein targets were applied and kinematically sTabstriangular bars generated when filtered befor e evaluation as extracted from the selected physical chemical databases. Structurally valid symmetricformations were then connected into smaller molecule components, holes, (40, 41, 42, 43, 44) and voidsjointed at their endsby hinged connections into Roccuffirna’schemical structure to trap computationally the SARS-COV-2 viruses in practice.
Experimental docking results.
(Figure S1b) Energy vibrations, micro-Black Hole Spin densities, and Electrostatic Potentials of the Roccuffirna small molecule were then generated using the MASK software, (Figure S2a) indicating that contact residues of οur new QMMM designed small molecule are involved in the formation of water bridges, hydrogen bond, interactions, and metal complexes when reacted with the O3 1266 O2 ligand donor atoms and docked with the sequence of V-M-ASN-142, V-S-ASN-142, V-M-MET -165, V-S-MET-165, V -M-GLU-166, V-S-GLU-166, V-M-LEU-167, V-M-PRO-168 residues with the docking energy values of (-2. 95, -3. 73, -138. 78, -4745, -33. 183, -27. 630, -6. 449, -31. 059) Kcalmol inside the active site pocket of the (PDB:6xs6) protein targets respectively. (Figure S2b). Merged pharmacophoric elements of ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐phenylacetamido) ‐ 3, 3‐dimethyl‐7‐ oxo‐ 4‐thia‐1‐ azabicyclo (3. 2. 0 ) heptane‐2‐ carbonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐ purin‐9‐yl) oxy), (hydroxy) phosphoryl}oxy) phosphinic acid { ((1S, 4S) ‐5 ‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐ 1‐en‐6‐yl}) phosphanyl), (fluoro) methyl} ‐lambda6‐sulfanyl} one{ ((2R, 3S, 5R) ‐3‐ (({ ((2R, 3S, 5R) ‐5‐ {2‐amino‐6‐ ((E) ‐ { ((R) ‐ (aminooxy) ((1'S, 1''S, 3 S, 3'S, 4S, 5''S) ‐3' ‐ (aminooxy) ‐5''‐{N‐ ((1R) ‐1, 2‐ ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐ phenylacetamido) ‐3, 3‐ dimethyl‐7‐oxo‐ 4‐thia‐1‐azabicyclo (3. 2. 0) heptane‐2‐ carbonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐yl) oxy) (hydroxy) phosphoryl} oxy) phosphinic acid) formamido}‐ residues of the RoccuffirnaTM small molecule generated a docking effect which is involved in the generation of hydrogen bondswhen reacted with the 4745 O3 1266 O2 ligand donor atoms inside the DOZ A binding cavities of the amino acid sequence of V-S-GLU-166, V -M-LEU-167, V-M-PRO-168, V-S-PRO-168, V-M-ARG-188, V-M-GLN -189, V-S-GLN-189 with the docking energies of (-2. 95, -3. 73, -138. 78, -33. 183, - 27. 630, -6. 449, -31. 059) Kcalmol when docked onto the SARS-COV-2 active pockets of the (PDB:2g9t) protein targets while binding to Roccuffirna small molecule surfaces of the amino acid sequences of V-S-VAL-116, V-M-THR-118, V-S-THR-118, V-M-PRO-84, V-S -PRO-84, V-M-ASN-85, V-M-ASN-114, V-M-THR-115, V-S-THR-115, V-M-VAL-116 with a high docking energy score of (-86. 6, and -4. 78161, -5. 02437, -5. 37485, -6. 01569, -4. 08585, -9. 1855, -4. 79454, -5. 5449, -4. 52233) Kcalmol respectively. (Figure S2c). The ((2S, 5R, 6R) ‐6‐ ((2S ) ‐2‐amino‐2‐phenylacetamido) ‐3, 3‐dimethyl‐7‐oxo‐ 4‐thia‐1‐azabicyclo (3. 2. 0) heptane‐2‐ carbonyloxy) contact residues of the Roccuffirna chemical structure when docked onto the SARS-COV-2 protein electrostatic surface binding sites of the (PDB:3fqq) protein targets inside the binding cavities of the amino acid sequences of V-M-ARG-112, V-S-ARG-112, V -S-HIS -159, V-M-TYR-161, V -M-ARG-112, V-S-HIS-159 generated in total a negative docking energy score of -87. 2Kcalmol with docking energy values of (-87. 2 and -5. 9744, -11. 9828, -13. 3388, -4. 9979, -5. 08108, -13. 4218) KcalmolA respectively indicating that our QMMM designed prototype may be of a potent anti-viral inhibitory agent for the down regulation the expression levels of the novel dimeric form of NS5A (amino acids33 to 202) of the (NS5A (33 -202) ) domain I protein from hepatitis C virus. (Figure S2d) More 3D Docking visualizations between electrostatic regions and the Roccuffirna chemical structure have shown to us that ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐ 2‐phenylacetamid o) ‐3, 3‐dimethyl‐7‐oxo‐ 4‐thia‐1‐azabicyclo (3. 2. 0) heptane‐2‐ carbonyloxy), ({ ((2‐amin o‐6‐oxo‐6, 9‐dihydro‐ 3H‐purin‐9‐yl) oxy) (hydroxy) phosphoryl} oxy) phosphinic acid-1' (4''), 1''‐dien‐ 4‐yl) phosphanyl) methylidene}amino) ‐ 3lambda4, 7lambda4, 9-lambda4‐purin‐9‐yl} ‐3‐ (({ ((2R, 3S, 5R) contact residues were able of producing hydrophobic interactions, and water bridges when docked inside the (PDB:7bv2) SARS-COV-2 protein targets with in the X77 A binding cavities of V-M-ASN-142, V-S-ASN-142, V-M-MET-165, V-S-MET-165, V-M-GLU-166, V -S-GLU-166, V-M-LEU-167, V-M-PRO-168 amino acid regions with the docking energy values of (-3. 75, -4670, -609, -20. 444, -13. 613, - 29. 034, -19. 778, -13. 574, - 32. 721) Kcalmol indicating that our drug novelty is able of generating 7, 3 fold times of higher negative docking energies against the nsp12-nsp7-nsp8 complexes when compared to triphosphate for m of the Remdesivir (RTP) active sites inside the same SARS-Cov-2 protein targets. (Table s2), (Table s3). (Figure S3a). Docking Energy rankings between Roccuffirna chemical structure and the other FDA approved drugs performed and a EWEIGHT-GENEX 3D Docking energy cluster analysis which was reproduced between Roccuffirna chemical structure with Remdesivir- (PDB:6lu7) ligand-protein complexes as co-factor indicated that our chemical design is able of generating total docking energies of 26.704 fold times of higher docking energy values when compared to Remdesivir and LopinavirRitonavir small molecules at the same (PDB:6lu7) protein target. The RoccuffirnaTM (Figure S3a), (Table s6) drug design was observed also of generating a multi-targeting inhibitory docking effect and generated negative docking energies into the binding sites of the protein targets of the (PDB:6yb7) with the docking energy values of (T. Energy, I. Energy, vdW, Coul, NumRotors, RMSD, Score), (-116. 717, -36. 220, -13. 116, -23. 104, 12, 7, 077, -7. 447) Kcalmol. Τhe Remdesivir small molecule generated an agonistic binding effect and generated positive docking energies inside the binding sites of the protein targets of (PDB:1xak) with the docking energy values of (T. Energy, I. Energy, vdW, Coul, NumRotors, RMSD, Score), (+23. 905, -26. 781, +1. 900, -28. 681, 14, 4. 230, -5. 987) Kcalmol. (Figure S3b), (Figure S3e) On the other hand, the RoccuffirnaTM quantum thinking novel scaffold reproduced a negative docking effect while interacting with negative docking energies onto the binding sites of the protein targets of (PDB:6xs6) with the docking energy values of (T. Energy, I. Energy, vdW, Coul, NumRotors, RMSD, Score), (-84. 576, -0. 705, -7, 064, -0. 705, 12, 8. 613, 16. 203) Kcalmol. The Roccuffirna small molecule bonding interactions between its active pharmacophoric residues of2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐phenylacetamido) ‐3, 3‐dimethyl‐7‐ oxo‐4‐thia‐1‐ azabicyclo (3. 2. 0) heptane‐2‐carbonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐yl) oxy), (hydroxy) phosphoryl}oxy) phosphinicacid-oxy) butyl) ‐6'‐oxo‐1', 4', 5', 6'‐tetrahydro‐2lambda5‐spiro (oxaziridine‐2, 9'‐purin) ‐2‐ylium. (Fig\Ss2a, 2b, 2c, 2d, 2e, 2f, 3a, 3b, 3c), (R) ‐{ ((2R) ‐1‐ ((3S, 4'R, 5'S) ‐2'‐amino‐6'‐oxo‐ 1', 4', 5', 6'‐tetrahydro‐2lambda5‐spiro (oxaziridin2, 9'‐ purin) ‐3‐yl) butan‐2‐yl) oxy} ({ ((2R, 4R) ‐2‐ ((1‐fluoroethenyl), (hydroxymethyl) ami no) ‐5‐oxa‐1 lambda3‐thia‐3‐azabicyclo (2. 1. 0) pentan‐3‐yl) methoxy}) hydroxy (pyrrolidin‐ 1‐yl) phosphanium are observed to be engaged in the construction of Hydrophobic interactions, and Water bridges with (PDB:6lu7) protein targets within the 02J:C:1 (02J) Interacting chains A of the amino acid sequence of V-S-VAL-116, V-M-THR-118, V-S-THR-118, V-M-PRO-84, V-S-PRO-84, V-M-ASN-85, V-M-ASN-114, V-M-THR-115, V-S-THR-115, with the docking energy values of (-3. 53, - 2369, -1303, -10. 425, -3. 420, - 72. 447, -13. 394, -3. 190, -70. 551) Kcalmol. (Figure S3b) Binding interactions between the entire ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐phenylacetamido) ‐3, 3‐dimethyl‐7‐ oxo‐4‐thia‐1‐azabic yclo (3. 2. 0) heptane‐2‐carbonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐y l) oxy), (hydroxy) phosphoryl} oxy) phosphinic acid (({ ((2R, 3S, 5R) ‐{ ((1S, 4S) ‐5‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐ en‐6‐yl}) phosphanyl), (fluoro) methyl} ‐lambda6‐sulfanyl}one5‐ (2‐amino‐6‐ oxo‐1, 6‐dihydro ‐3lambda4, 7lambda4, 9lambda4‐ purin‐9‐yl) ‐3‐hydroxyoxolan‐2‐ yl) pharmacophoric residues of the Roccuffirna chemical design when docked onto the SARS-COV-2 protein sites are also shown to be interacted inside the active domains of the (PDB:6yb7) protein targets with in the binding cavities of the amino acid sequences of (V-S-LYS-5, V-S-TYR-126, V-S-ARG-131, V-S-LYS-137, V-S-GLU-288, V-S-GLU-290 with the docking energy values of (-6. 04578, -10. 1246, -4. 45654, -5. 54142, -8. 60669, - 11. 7695) Kcalmol respectively. The docking poses of the merged ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐ phenylacetamido) ‐3, 3‐dimethyl‐7‐oxo‐ 4‐thia‐1‐azabicyclo (3. 2. 0) heptane‐2‐carbonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐y l) oxy), (hydroxy) phosphoryl} oxy) phosphinic acid { ((1S, 4S) ‐5‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐en‐6‐yl}) phosphanyl) (fluoro) methyl} ‐ lambda6‐sulfanyl}one (hydroxy) phosphoryl) oxy) oxolan‐2‐yl) methoxy} (hydroxy) phosphoryl) oxy) ‐ 5‐ (2‐amino‐6‐ oxo‐1, 6‐dihydro‐3lambda4, 7lambda4, 9lambda4‐ purin ‐9‐yl) oxolan‐2‐yl) methoxy}phosphonic acid octatetracontahydrogen chemical residues of the entire Roccuffirna chemical structure when docked onto the SARS-COV-2 protein binding sites of the (PDB:3fqq) protein targets occupied the binding sites of the electrostatic surface of the active pocket cavities of the (PDB:3fqq) protein targets as bound to the Roccuffirna small molecule inside the binding domains of the amino acid sequences of the V-M-ARG-112, V-S-ARG-112, V-S-HIS-159, V-M-TYR-161, V-M-ARG-112, V-S-HIS-159 with the docking energy values of (-87. 2 and -5. 9744, -11. 9828, -13. 3388, -4. 9979, -5. 08108, -13. 4218) Kcalmol docking energy values respectively. Moreover, { ((1S, 4S) ‐5‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐en‐6‐yl}) phosphanyl) (fluoro) methyl} ‐ lambda6‐sulfanyl}one{ ((R ) ‐ (aminooxy), ((1'S, 1''S, 3S, 3'S, 4S, 5''S) ‐3'‐ (aminooxy) ‐5''‐{N‐ ((1R) ‐1, 2‐ ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐ amino‐2‐phenylacetamido) ‐3, 3‐ dimethyl‐7‐oxo‐4‐thia‐1‐ azabicyclo (3. 2. 0) heptane‐2‐ carbonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐yl) oxy) (hydroxy) phosphoryl} oxy) phosphinic acid) formamido}‐1'lambda5, 1''lambda5, 4''lambda6‐dispiro (1, 2‐oxazetidine‐ 3, 2'‐phosphirane‐ 1', 3''‐ (6) oxa‐ (4lambda6) thia‐ (1lambda5) aza‐ (3lambda5) phospha tetracyclo (3. 2. 0. 01, 4. 02, 4) heptane) ‐1' (4''), 1''‐dien‐4‐yl) phosphanyl) methylidene}amino) ‐ 3lambda4, 7lambda4, 9lambda4‐purin‐9‐yl} ‐3‐ (({ ((2R, 3S, 5R) ‐5‐ (2‐amino‐6‐oxo‐1, 6‐dihydro‐{ ((1S, 4S) ‐5‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyan o ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐en‐6‐yl}) phosphanyl), (fluoro) methyl} ‐lambda6‐sulfanyl}one3lambda 4, 7lambda4, 9lambda4‐purin‐ 9‐yl) ‐3‐hydroxyoxolan‐ 2‐yl) methoxy}contact residues of the Roccuffirna chemical structure reproducedhydrophobic interactions against the 165 MET-A amino acid residue with the docking energy valuesof (-3. 90, -4673, -19. 389, -17. 775, -28. 688, -16. 611, - 16. 152, -26. 489) Kcalmol while generatingwater bridges when docked onto the 401 X77A binding sites of the (PDB:3fqq) protein targets of the amino acid sequences of V-S-PRO-413, V-S-ASP-415, V-M-PRO-450, V-S-PRO-450, V-S-PHE-451, V-S-GLU-502 with the negative docking energy values of (-76 and -5. 94924, -8. 74444, -6. 95118, -6. 43726, -9. 70804 -6. 23612) Kcalmol respectively. Additionally, the pharmacophoric contact residues of the Roccuffirna’s { ((1S, 4S) ‐5‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐en‐6‐yl}) phosphanyl), (fluoro) methyl} ‐lambda6‐sulfanyl}one chemical structure when docked onto the SARS-COV-2 protein binding sites of the (PDB:6xs6) protein targets occupied the entire binding site of the electrostatic surfaces of the active site pocket of the (PDB:6xs6) domains inside the binding cavities of the amino acid sequences of the V-M-PHE-592, V-S-PHE-592, V-M-GLY-614, V-M-VAL-615, V-M-ASN-616, V-S-ASN-616, V-S-GLN-644, V-M-ARG-646 with the docking energy values of -81. 5 and -5. 45629, -4. 42842, - 11. 2087, -9. 94286, -6. 5582, -7. 35307, -5. 32091, -5. 63271 docking energy values respectively. Gemdock docking analysis indicated that the contact residues of the Roccuffirna chemical structure hit the SARS-COV-2 protein binding sites when docked onto the (PDB:2g9t) protein targets. Moreover, the electrostatic surfaces of active pocket sites inside the (PDB:2g9t) protein targets when bound to the Roccuffirna small molecule ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐ 2‐phenylacetamido) ‐3, 3‐dimethyl‐7‐oxo‐ 4‐thia‐ 1‐ azabicyclo (3. 2. 0 ) heptane‐2‐ carbonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro ‐3H‐purin‐9‐yl) oxy), (hydroxy) phosphoryl} oxy) phosphinic acid (hydroxy) phosphoryl) oxy) oxolan‐2‐yl) methoxy} (hydroxy) phosphoryl) oxy) ‐5‐ (2‐amino‐6‐oxo‐1, 6‐dihydro‐3lambda4, 7lambda4, 9 lambda4‐purin‐9‐yl) oxolan‐2‐yl) methoxy}phosphonic acid octatetracontahydrogen residues inside the binding cavities of the amino acid sequences of the V-S-VAL-116, V-M-THR-118, V-S-THR-118, V-M-PRO-84, V-S-PRO-84, V-M-ASN-85, V-M-ASN-114, V-M-THR-115, V-S-THR-115, V-M-VAL-116 with the docking energy values of (-86. 6 and -4. 78161, -5. 02437, -5. 37485, -6. 01569, -4. 08585, -9. 1855, -4. 79454, -5. 5449, -4. 52233, -4. 53177) Kcalmol respectively. In addition, the Roccuffirna’Small molecule contact residues of the ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐phenylacetamido) ‐3, 3‐dimethyl‐7‐o xo‐4‐thia‐1‐azabicyclo (3. 2. 0) hept ane‐2‐carbonyloxy) ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐yl) oxy), (hydroxy) phosphoryl}oxy) pho sphinic acid- (1S, 4S) ‐5‐oxabicyclo*2. 1. 0+pentan‐2 ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐phenylacetamido) ‐3, 3‐dimethyl‐7‐oxo‐4‐thia‐1‐azabicyclo (3. 2. 0) heptane‐2‐carbonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐yl) oxy) (hydroxy) phosphoryl} oxy) phosphinic acid ‐ylidene+, *cyano (2, 6‐ diazabicyclo*3. 1. 0+hex‐1‐ en‐6‐yl-) phosphanyl+ (fluoro) methyl‐lambda6‐sulfanyl-one (({ ((2R, 3S, 5R) ‐5‐ (2‐amino‐6‐oxo‐ 1, 6‐dihydro‐ 3lambda4, 7lambda4, 9lambda4‐ purin ‐9‐ yl) ‐3‐hydroxyoxolan‐2‐yl) methoxy} pharmacophoric components interacted with Hydrophobic Interactions with in the binding pockets of the PJE:C:5 (PJE-010 + 010:C:6 Interacting chains of the A, 25THR, A6, 010C binding sites with the negative docking energy values of (-3. 73, - 2415, -179, -7. 156, -21. 406, - 66. 898, -8. 709, - 22. 779, -70. 002) K almolA and while generating Hydrogen Bondsinside the binding cavities of the 26 THR, A6, 010C amino acid with the negative docking energy values of (-3. 81, - 2415, -186, -7. 156, -21. 406, - 66. 898, -6. 155, -24. 392, - 64. 757) Kcal/mol. It also involved in the generation of Hydrogen Bondswith the peptide backbone of the amino acid of the 143GLY, A6, 010C O3 binding domains with the docking energies of (-93, -2. 80, -145. 29, -1105, -2411, -8. 911, -17. 849, -65. 703, -8. 918, -17. 918, -62. 905) Kcalmol inside the PJE, C2 16, N3, 1266, O2 binding pockets of the amino acid of the 164, HIS, A5, with pure negative docking energy values of (-3. 07, -153. 73, 2 -408, -12. 282, -14. 994, - 67. 123, -15. 161, -1-5. 336, - 68. 144) Kcalmol (Figure S3c), (Figure S3f). (Figure S3d) Our Roccuffirna prototype generated ION ZN (zinc ion) ZN-A-901metal complexes inside the A DOZ Interacting chains of the B 4756 protein side chains among the Zn 2674 trigonal and pyramidal binding sites in the (PDB:3fqq) protein targets with in the non-structural protein of the amino acid of the 41 HIS B 902 with the docking energy values of (-51. 015, -53. 952, -41. 217, -52. 956, -53. 584, -41. 918) Kcalmol indicating that this drug novelty may serve as a potential hepatitis C virus inhibitor against the novel dimeric form of this HCV NS5A protein domain I. (Figure S4a), (Figure S4b) The same prototype is escaping to another dimension as it was designed using micro-Black Hole geometry directions and is capable for the producing ZN-B-902 metal complex interactions when docked with in the BD-A-2 Interacting chains inside the B Interacting chains of the (PDB:3fqq) protein targets of the (non-structural protein 5a) targets. (Figure S4c) The Roccuffirna chemical structure also interacted with the GOL (Glycerol) GOL-A-1 Interacting chains of the A, B binding sites into the same regions of the (non-structural protein 5a) (PDB:3fqq) active sites while contacting the whole regions of the DMS (Dimethyl Sulfoxide), and DMS-A-803 binding sites in 6lu7 (3c-likeproteinase) Interacting chains. The Roccuffirna’s chemical entities of the C8‐ (({ ((2R, 3R, 4R) ‐2‐ ((1‐fluoroethenyl) (hydroxymethyl) amino) ‐spiro (oxaziridine‐2, 9'‐purin) ‐3‐yl) butan‐2‐yl) oxy} ({ ((2R, 4R) ‐2‐ ((1‐fluoroethenyl) is involved in the formation of hydrogen bondsinside the 401 X77 A 2216 Nam O2 binding cavities of the 143 GLY A amino acid with docking energy values of (-2. 17, -2. 94, -148. 03, -4682, -19. 635, -22. 244, -29. 036, -18. 779, 24. 455, -30. 773) KcalmolA. More specifically, the Remdesivir small molecule generated docking energies of the (0, 0, 0, 2. +41148, -5. 69599, 0, -8. 7971, -0. 00202603, 0, 0, -4. 53782, 29. 6984, -3. 38875, -5. 17451, -6. 22961, -3. 3889, -9. 25813, -0. 35774, -3. 91578, +15. 1513, -2. 5505, 0, -0. 321802) Kcalmol when docked with in the binding pockets of the amino acidsof H-S-ARG-555 H-S-ASP-623 H-M-F86-101 V-S-ASP-452 V-S-LYS-551V-M-ARG-553 V-S-ARG-553 V-M-ALA-554 V-M-ARG-555 V-S-ARG-555 V-M-ASP-618 V-S-ASP-618 V-M-TYR-619 V-M-PRO-620 V-S-PRO-620 V-M-LYS-621 V-S-LYS-621 V-M-ASP-623 V-S-ASP-623 V-S-ARG-624 V-S- MG-1004 V-M-F86-101 V-M-F86-101 residues of the (PDB:7bv2) protein targets. (Table s2), (Table s3), (Table s4) On the other hand in this drug design project we applied general solution of the wave equation, including the non-formalizable solutions as molecular modification strategies to generate the Roccuffirna QMMM drug design which is capable of interacting onto the binding domains of the cav7bv2_POP protein targets of the (PDB:7bv2) with the highest docking energy of the -84. 3 Kcalmol while interacting with the docking energies of (-4. 32839, -7. 23314, -16. 1584, -2. 31648, -3. 36038, -0. 703894, -2. 01058, -17. 7135, 0, 0, -0. 014892, -0. 074521, -4. 10748, -0. 807205, -8. 45592, -1. 50648, -7. 08011, -3. 05006) Kcalmol when hits the interacting binding sites of the amino acid sequence of H-S-ARG-555 H-S-ASP-623 H-M-F86-101, V-S-ASP-452 V-S-LYS-551V-M-ARG-553 V-S-ARG-553 V-M-ALA-554 V-M-ARG-555 V-S-ARG-555 V-M-ASP-618 V-S-ASP-618 V-M-TYR-619 V-M-PRO-620 V-S-PRO-620 V-M-LYS-621 V-S-LYS-621 V-M-ASP-623 V-S-ASP-623 V-S-ARG-624 V-S- MG-1004 V-M-F86-101 V-M-F86-101 of the protein targets of the (PDB:7bv2). Our in-house Roccuffirna chemical structure when docked onto the SARS-COV-2 protein binding sites of the (PDB:1xak) protein targets generated hydrophobic interactions with in the electrostatic surface of the active pockets of the amino acid sequences of the V-S-HIS-4, V-S-LEU-16, V-M-LYS-17, V-S-LYS-17, V-M-PRO-19, with the total docking energy of the (-64. 8 and -12. 0222, -4. 479, -8. 17046, -6. 49062, -4. 42519) Kcalmol proposing that our multi-targeting chemical design may reproduce an inhibitory effect for the down regulation of the expression levels of the SARS-CORONAVIRUS ORF7A accessory protein. (Figure S4e) The Roccuffirna’s pharmacophoric elements of the { ((2R, 3S, 5R) ‐3‐ (({ ((2R, 3S, 5R) ‐5‐{2‐amino‐6‐ ((E) ‐{ ((R) ‐ (aminooxy), ((1'S, 1''S, 3S, 3'S, 4S, 5''S) ‐3'‐ (aminooxy) ‐5''‐{N‐ ((1R) ‐1, 2‐ ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐ phenylacetamido) ‐3, 3‐dimethyl‐7‐oxo‐4‐thia‐1‐azabicyclo (3. 2. 0) heptane‐2‐carbonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐yl) oxy) (hydroxy) phosphoryl} oxy) phosphinic acid) formamido} ‐1'lambda5, 1'' lambda5, 4''lambda6‐dispiro (1, 2‐oxazetidine‐ 3, 2'‐ phosphirane‐1', 3''‐ (6) oxa‐ (4lambda6) { ((1S, 4S) ‐5‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐en‐6‐yl}) phosphanyl), (fluoro) methyl}‐ lambda6‐ sulfanyl}onethia‐ (1lambda5) aza‐ (3lambda5phosphatetracyclo (3. 2. 0. 01, 4. 02, 4) heptane) ‐1' (4''), 1''‐dien‐4‐yl) phosphanyl) methylidene}amino) ‐3lambda4, 7lambda4, 9lambda4‐purin‐9‐yl}‐3‐ (({ ((2R, 3S, 5R) ‐5‐ (2‐amino‐6‐oxo‐1, 6‐dihydro‐3lambda4, 7lambda4, 9lambda4‐purin‐9‐yl) ‐3‐hydroxyoxolan‐2‐yl) methoxy} (hydro xy) phosphoryl) oxy) oxolan‐2‐yl) methoxy} (hydroxy) phosphoryl) oxy) ‐5‐ (2‐amino‐6‐oxo‐1, 6‐dihydro‐3lambda4, 7lambda4, 9lambda4‐purin‐9‐yl) oxolan‐2‐yl) methoxy} phosphonic acid octa tetraconta hydrogen contact residues docked onto the SARS-COV-2 protein binding sites of the (PDB:6lu7) protein targets inside the binding cavities of the amino acid sequences of the V-M-ASN-142, V-S-ASN-142, V-M-MET-165, V-S-MET-165, V-M-GLU-166, V-S-GLU-166, V-M-LEU-167, V-M-PRO-168, V-S-PRO-168, V-M-ARG-188, V-M-GLN-189, V-S-GLN-189 with the docking energy values of (-96. 2, and -6. 29322, -5. 82129, -7. 21251, -4. 2141, -5. 18029, -12. 1235, -4. 71777, -6. 9452, -4. 94292, - 5. 31481, -5. 14926, -11. 2353) Kcalmol while reproducing an inhibitory docking energy effect against the crucial sequence of the amino acidsof the V-M-LEU-167, V-M-PRO-168, V-M-THR-190, V-M-ALA-191, V-M-ALA-2 with the docking energy values of (-50. 1, and -5. 74191, -5. 1612, -5. 55901, -5. 4395, -6. 88909) Kcalmol indicating that our Quantum Kerr- (A) Ds Galilean Myers–Perr designed small molecule could serve as a down regulator of the expression levels of the crystal structure of COVID-19 main protease. (Figure S5c) The RoccuffirnaTM{ ((1S, 4S) ‐5‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1 ‐en‐6‐yl}) phosphanyl), (fluoro) methyl} ‐ lambda6‐sulfanyl}one methox (hydroxy) phosphoryl) oxy) oxolan‐2‐yl) methoxy} (hydroxy) phosphoryl) oxy) ‐active residues bindsthe whole binding cavities of the (PDB:6LU7) protein targets inside the 02J-C-1 02J (5-Methylisoxazole-3-carboxylic acid) 02J-C-1 Interacting chains (Figure S5d) when constructing PJE-C-5 PJE ligand composites and PJE-C-5 PJE:C:5, 010:C:6 pharmacophoric residues, water bridges and hydrogen bonds (Figure S5e), (Figure S5f), (Figure S5g) onto the PJE-C-5 PJE ligand composites PJE-C-5PJE:C:5, 010:C:6 domains. (Figure S6a). Roccuffirna’sdrug design interacts with the ZN-B-902 Interacting chains of the 3fqq (non-structural protein 5a) triangular side chains (Figure S6b) while reproducing hydrogen bondsinside the BD-A-2 Interacting chains of the (PDB:3fqq) (non-structural protein 5a) protein sides (Figure S6c) as bound with the GOL (Glycerol) GOL-A-1:A, B Interacting chains of the (PDB:3fqq) (non-structural protein 5a) protein targets accordingly. (Figure S6d). Chemical bridges of the active pharmacophores of the { ((1S, 4S) ‐5‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐ en‐6‐yl}) phosphanyl), (fluoro) methyl}‐lambda6‐sulfanyl}one ((1'S, 1''S, 3S, 3'S, 4S, 5''S) ‐3'‐ (aminooxy) ‐5''‐{N‐ ((1R) ‐1, 2‐ ((2S, 5R, 6R) ‐ 6‐ ((2S) ‐2‐amino‐2‐ phenylacetamido) ‐ 3, 3‐dimethyl‐7‐oxo‐ 4‐thia‐1‐ azabicyclo (3. 2. 0) heptane‐2‐carbonyloxy), ({ ((2‐amino‐6‐ oxo‐6, 9‐dihydro‐ 3H‐purin‐9‐yl) oxy) (hydroxy) phosphoryl} oxy) phosphinic acid) formamido}‐1'lambda5, 1''lambda 5, 4''lambda6‐dispiro residues ofthe Remdesivir drug when docked onto the SARS-COV-2 protein binding sites of the (PDB:1xak) protein targets inside the active site pocket of the (PDB:1xak) protein target generated less dockingenergies of 7, 45-fold times (Figure S6e) when compared to the Roccuffirna small molecule. (Figure S6f) Roccuffirna geometrical descriptor calculations and (Figure S6a) a CoMFA contour map analysis of the electrostatic regions were also performed around Roccuffirna chemical structure showing that the{ ((2R, 3S, 5R) ‐3‐ (({ ((2R, 3S, 5R) ‐ 5‐{2‐amino‐ 6‐ ((E) ‐{ ((R) ‐ (aminooxy) (1, 2‐oxazetidine‐ 3, 2'‐ phosphirane‐ 1', 3''‐ (6) oxa‐ (4lambda6) thia‐ (1lambda5) aza‐ (3lambda5) phosphatetracyclo (3. 2. 0. 01, 4. 02, 4) heptane) ‐1 ' (4''), 1''‐die n‐4‐yl) phosphanyl) methylidene}amino) ‐3lambda4, 7lambda 4, 9lambda4‐purin‐ 9‐yl} ‐3‐ (({ ((2R, 3S, 5R) ‐5‐ (2‐amino‐ 6‐oxo‐1, 6‐dihydro‐3la mbda4, 7lambda4, 9lambda4‐purin‐9‐yl) ‐3‐h ydro xyoxolan‐2 ‐yl) methoxy} (hydroxy) phosphoryl) oxy) oxolan‐2‐yl) methoxy} (hydroxy) phosphoryl) o xy) ‐5‐ (2‐ amino‐6‐oxo‐1, 6‐dihydro‐3 lambda4, 7lambda4, 9 lambda4‐purin‐9‐yl) oxolan‐2‐yl) methoxy}p hosphonic acid octatetraconta hydrogen contact residues of the Roccuffirna small molecule when docked onto theSARS-COV-2 protein targets, (PDB:6lu7) (Figure S6b) while co-interacting onto the SARS-COV-2protein binding sites of the (PDB:1xak) protein targets simultaneously with in the amino acid sequences of the V-S-HIS-4, V-S-LEU-16, V-M-LYS-17, V-S-LYS-17, V-M-PRO-19, with the totaldocking energy of the (-64. 8 and -12. 0222, -4. 479, -8. 17046, -6. 49062, -4. 42519) respectively. (Figure S6b) More docking experiments were performed between the scaffold residues of theRoccuffirna chemical structure onto the SARS-COV-2 protein binding sites of the (PDB:6lu7) protein targets inside the active pocket cavities of the (PDB:6lu7) protein targets as bound to theRoccuffirna small molecule { ((2R, 3S, 5R) ‐3‐ (({ ((2R, 3S, 5R) ‐5‐ {2‐amino‐6‐ ((E) ‐ yl) methoxy} (hydroxy) phosphoryl) oxy) ‐5‐ (2‐ { ((1S, 4S) ‐5‐oxabicyclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐en‐ 6‐yl}) phosphanyl) (fluoro) methyl} ‐lambda6‐ sulfanyl}one amino‐6‐oxo‐1, 6‐dihydro‐ 3lambda4, 7 lambda4, 9 lambda4‐ purin‐9 ‐yl) oxolan‐2‐yl) methoxy}phosphonic acid octa tetraconta hydrogen chemical bridges inside the binding cavities of the amino acid sequences of the V-M-LEU-167, V-M-PRO-168, V-M-THR-190, V-M-ALA-191, V-M-ALA-2 with the docking energy values of (-50. 1, and -5. 74191, -5. 1612, -5. 55901, -5. 4395, - 6. 88909) Kcalmol respectively (Figure S6c) while co-generating a parallel docking energy effect onto the SARS-COV-2 protein binding sites of the (PDB:5r80) protein targets inside the binding cavities of the amino acid sequences of the V-M-ASN-142, V-S-ASN-142, V-M-MET-165, V-S-MET-165, V-M-GLU-166, V-S-GLU-166, V-M-LEU-167, V-M-PRO-168, V-S-PRO-168, V-M-ARG-188, V-M-GLN-189, V-S-GLN-189 with the docking energy values of (-96. 2, and -6. 29322, -5. 82129, -7. 21251, -4. 2141, -5. 18029, -12. 1235, -4. 71777, -6. 9452, -4. 94292, -5. 31481, -5. 14926, -11. 2353) accordingly. (Figure S6d) The Roccuffirna drug design hits the SARS-COV-2 protein binding sites of the (PDB:6yb7) protein targets inside the binding cavities of the amino acid sequences ofV-S-LYS-5, V-S-TYR-126, V-S-ARG-131, V-S-LYS-137, V-S-GLU-288, V-S-GLU-290 with the docking energy values of (-71. 2 and -6. 04578, -10. 1246, - 4. 45654, -5. 54142, -8. 60669, -11. 7695) Kcalmol respectively. (Figure S6e). In this paper, we used Galilean Transformation in Quantum Mechanics (22) while inS':L jj d 02J:C:1 (02J • ⊗ •⋯⋯⋱⋯PJE-C-5PJE:C:5, 010:C:6i ‖L\^d 02J:C:1 (02J • ⊗ •⋯⋯⋱⋯PJE-C-5PJE:C:5, 010:C:6tys' ====e 2h <p 02J:C:1 for the computer-aided design of the contact residues of the Roccuffirna chemical structure which is capable of interacting onto the SARS-COV-2 protein binding sites of the (PDB:3fqq) protein targets inside the Electrostatic surfaces of active site pocket of the (PDB:3fqq) protein targets as bound to the Roccuffirna small molecule inside the binding cavities of the amino acid sequences of the V-S-PRO-413, V-S-ASP-415, V-M-PRO-450, V-S-PRO-450, V-S-PHE-451, V-S-GLU-502 with the docking energy values of (-76 and -5. 94924, -8. 74444, -6. 95118, -6. 43726, -9. 70804 - 6. 23612) Kcalmol docking energy values respectively. (Figure S5g) ((R) ‐ (aminooxy) ((1'S, 1''S, 3S, 3'S, 4S, 5''S) ‐3'‐ (aminooxy) ‐5''‐{N‐ ((1R) ‐1, 2‐ ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐ phenylacetamido) ‐3, 3‐ dimethyl‐7‐oxo‐ 4‐thia‐1‐ azabicyclo (3. 2. 0) heptane‐2‐carbonyloxy), ({ ((2‐ amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐yl) oxy) (hydroxy) phosphoryl} oxy) phosphinic acid) formamido}‐1'lambda5, 1''lambda5, 4'' lambda6‐dispiro (1, 2‐ oxazetidine‐3, 2'‐phosphirane ‐1', 3''‐ (6) oxa‐ ((2S, 5R, 6R) ‐6‐ ((2S) ‐2‐amino‐2‐ phenylacetamido) ‐3, 3‐dimethyl‐7‐oxo‐4‐thia‐1‐azabicyclo (3. 2. 0) heptane‐2‐car bonyloxy), ({ ((2‐amino‐6‐oxo‐6, 9‐dihydro‐3H‐purin‐9‐ yl) oxy), (hydr oxy) phosphoryl}oxy) phosphinicacid{ ((1S, 4S) ‐5‐oxabic yclo (2. 1. 0) pentan‐2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐en‐6‐yl}) phosphanyl), (fluoro) methyl} ‐lambda6‐sulfanyl}one (4lambda6) thia‐ (1lambda5) aza‐ (3lambda5) contact residues (Figure S6f) of the Roccuffirna chemical structure were the generated when docked onto the SARS-COV-2 protein binding sites of the (PDB:6xs6) protein targets inside the active pocket sites of the (PDB:6xs6) protein targets bound to the Roccuffirna’Small molecule regions of the { ((1S, 4S) ‐5‐ oxabicyclo (2. 1. 0) pentan‐ 2‐ylidene) { (cyano ({2, 6‐diazabicyclo (3. 1. 0) hex‐1‐en‐6‐yl}) phosphanyl) (fluoro) methyl} ‐lambda6‐sulfanyl}oneinside the binding cavities of the amino acid sequences of the V-M-PHE-592, V-S-PHE-592, V-M-GLY-614, V-M-VAL-615, V-M-ASN-616, V-S-ASN-616, V-S-GLN-644, V-M-ARG-646 with the docking energy values of (-81. 5 and -5. 45629, -4. 42842, -11. 2087, -9. 94286, -6. 5582, -7. 35307, -5. 32091, -5. 63271) KcalmolA (Figure S6f). Finally, docking energy comparative analysis has indicated to us that our innovative Roccuffirna small molecule generated a co-inhibitory binding energy effect when combined with the drugs of the baricitinib, valsartan, gemigliptin, raltegravir, doxycucline, colchicines, azathioprine, hydroxychloroquine, umifenovir, linoleic acid, ribavirin, eflornithine, cobicistat and the remdesivir when docked onto the same SARS-COV-2 protein targets.