In silico Prediction of the Roccustyrna ADMET Properties and Bioactivity Score
The adequacy of therapeutic drugs mainly depends on the molecular property and bioactivity of the compounds (Shen et al., 2012). To predict the drug-likeness and bioactivity of the selected Roccustyrna (1S)-2‐{[(2S,3S,5R)‐5‐(2‐amino‐6‐oxo‐6,9‐dihydro‐3H ‐purin‐9‐yl ) ‐3‐hydroxyoxolan‐2‐yl]methyl}‐1‐({[(2S,4R,5R)‐2‐methyl‐2‐(methylamino)‐1,6‐diazabicyclo[3.2.0]heptan‐4‐yl]oxy}amino)‐2lambda5‐azaphosphiridine‐2‐carbonitrile, the in silico molecular property assessment was performed using the Molinspiration tool. This tool measures the milogP value (Octanol-water partition coefficient logP) and TPSA (Topological polar surface area) values of the compounds using Bayesian statistics. The result shows that the milogP value of the Roccustyrna small molecule was predicted as having ideal lipophilicity (logP < 5) (Han et al., 2019) in the aspect of absorption and permeation (Table 1c).
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 the (pdb:1xak) (Fig. 4a) 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, (Tables1a,1b,2a) The Roccustyrna chemical structure interacted into the binding sites of the protein targets (pdb:6w9c) (Fig. 4b) (Fig. 7e) 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. It 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, 70.551Kcal/mol. Our new QMMM designed small molecule named Roccustyrna 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. (Figs. 1a,1b, 4,5a,5b,5c, 5d,6a,6b,6c,6d,6e,7a,7b) The Roccustyrna’s active pharmacophoric site of the (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 Roccustyrna’s active pharmacophoric site of the dihydro‐3H‐purin‐9‐yl)‐3‐ hydroxyoxolan generated an inhibitory 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. 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, 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 (Figs. 1a,1b,4,5a,5b, 5c,5d,6a,6b,6c,6d,6e). 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 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. The Roccustyrna’s pharmacophoric active site of the 2-lambda5‐azaphosphiridin‐1‐ylium was engaged in hydrogen bonding interactions with the formation of hydrogen bonds inside the 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 O3 -8.911, 17.849, 65.703–8.918, 17.918, 62.905, 2.16 3.07 153.73 2408 N3 1266 O2 -12.282, 14.994, 67.123–15.161, 15.336, 68.144 Kcal/mol (Figs. 1a,1b,4,5a,5b, 5c,5d,6a,6b ,6c,6d,6e). 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 (Figs. 1a,1b,2a, 2b,2c,2d,3a, 3b,3c,4a,4b, 5a,5b,5c,5d,6a,6b,6c,6d,6e). 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, Sˆi=(σx,σy,σz)Iˆρs(t) = TrI(U(t)ρ (0)U†(t)),ρI(0) = I/2P(t′) = dΔM(t′) ΔM = f(t′)dt′,ρ¯s=∫ −∞0f(t′)ρs(t′)dt′=∫0 ∞ f(t)ρs(t)dt,∫−∞0f(t′)dt′=∫0 ∞ f(t)dt = 1ρ¯sρ¯sρ¯sρ¯ s(,π/2)ρ¯sρs(0) ρ¯sQFI≈∑i = 01Re(ρi12)2(1ρi11 + 1ρi22)+ (ρi11 − ρi22)2ρi11 + ρi22,ρ1ij=〈φi 〈1 ρs(0) φj〉 1〉ρ0ij=〈φi 〈0 ρs(0) φj〉 0〉 0〉 1〉H1 = γB0⋅Sˆ1Re(ρi12)ρi12ρs(0)ρ¯s S〉=12( 〉− 01〉)30%ρs(0)ρ¯s = H⊗m 0〉⊗m = H⊗H⊗⋯⊗H 00⋯0 = 12( 0 + 1)⊗12( 0 + 1)⊗⋯⊗12( 0+ ) = 12 m( 00⋯0〉+ 00⋯1〉)+⋯+( 11⋯1). In this article we generated the RoccustyrnaTM small molecule (Figs. 1a,1b,4,5a,5b,5c,5d,6a,6b,6c,6d,6e) with the Geometrical Descriptors of the: Dreiding energy = 305,20 kcal/mol, MMFF94 energy = 35,06 kcal/mol, Minimal projection area = 66,49, Maximal projection area = 123,65 Minimal projection radius = 5,71 Maximal projection radius = 9,24 Length perpendicular to the max area = 1,29 Length perpendicular to the min area = 19,04 van der Waals volume = 409,41 Donor count = 5 Donor sites = 6 Acceptor count = 11 Acceptor sites = 14. (Fig. 7a) 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, (pdb:3fqq) hits the positively charged groups and red regions favored by negatively charged groups within the binding domains sequence 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. (Fig. 7b) 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 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, (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. (Fig. 7c) 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, (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. (Fig. 7d) In addition, 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, (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.(Fig. 7e) The Roccustyrna small molecule hits also the entire binding domains of the SARS-COV-2 protein targets, (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. 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, -6.28532Kcal/mol. 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.