INTRODUCTION
( 1, 2, 3) The COVID - 19 viral infectious which
emerged in China at the end of 2019 previously provisionally named 2019
- nCoV or 2019 novel coronavirus was officially declared in March 2020 a
pandemic by the World Health Organization ( WHO) and is
accountable for many fatal cases. ( 2, 4, 5) On January
202, the WHO committee declared a global health emergency ( 3, 4
- 6) based on the rate of the increasing spread of the
infection ( 4, 5 - 7) in the range 2.0 - 6.0 with a
reproductive number ( rN) 5, 4 higher than SARS and
Middle East respiratory Syndrome Coronavirus ( MErS)respectively ( 8) with fatality rate of about 4%.( 1 - 4) Collaborative efforts for Genomic
characterization by using a simple DNA cryptography genetic code
according to the main dogma of biology have been published that takes
plaintext for communicating information through a process of
DNA→rNA→Amino Acid coding. researchers in 2010 published a Cryptographic
DNA - mobile based Code for Secure Networks Scheme in which binary
plaintext is translated to text via a substitution wrapping code,
introns are inserted into DNA hierarchal text structure on the general
processes of gene expression by the transcription complex and a binary
key is passed to the receiver over a secure channel to provide the
details of the intron insertion. We cannot imagine a world without
cryptography anymore. Whether it is to protect our banking information,
e - mail, or phone calls, cryptography is a vital part of our digital
infrastructure. Modern - day cryptography is usually split up into two
phases. In the key exchange phase, an algorithm such as Elliptic Curve
Diffie - Hellman key exchange ( ECDH) or rSA is used to
establish a shared secret key that can be used in an asymmetric
encryption algorithm in the second phase. These algorithms have been and
continue to be well - studied and have proven themselves to be secure if
instantiated with proper parameters and implemented securely. Nowadays
most people favor using cryptographic keys over sticks and more
intricate cryptographic algorithms than wrapping at an angle. This opens
the door to new types of cryptographic attacks. Attack avenues can
roughly be divided into two categories: attacks on theoretic algorithm
by trying to recover the key or message by using public information
provided on the algorithm, and attacks on the implementation of the
algorithm, which look at the soft - or hardware - specific properties.( 5, 6, 7 - 9) Evolution, phylogeny, high contagion
rates, molecular epidemiology, of SARS coronavirus, and epidemiology
from scientists worldwide are underway to understand the rapid spread of
the novel coronavirus ( CoVs) , and to develop effective
coding drug - protein - gene interactions of personalized intervention
options for control, characterize, and prevention of viral outbreaks,
and various devastating diseases. ( 1 - 10)Coronaviruses are positive - single stranded, and through transcription
and ultimately translations enveloped large rNA viruses that infect
humans and a wide range of animals. ( 4, 6, 7, 8, 9,
10) In Latin, Corona means ―crow based on their shapes. As a
comprehensive compendium and megadiverse country, Brazil accounts for
10–20% of known living species of available biogeochemical information
in the world. However, a major part of the biological and chemical
biodiversity in Brazil’s natural products remains unexplored( 2– 13, 14, 15, 16, 17) Molecular structures as a
protein code ( cipher - protein) were determined in
heterodox interpretations ( 22) by solving the time -
independent ( 21 - 22) Schrödinger equation: QM
methods, vertex prizes, and edge costs including ab initio
Density
Field Theories ( DFT) ( 23) has become a common
approach as a quantum - many body premium technique and semi - empirical
computational scheme in place ( 24) of the quantum
processor and docking energy used for studying molecule structure under
QM simulated sampling error among other quantitative understanding
observables. Density Field Theories ( DFT) is
continuously increasing for more systematic and less expensive methods( 25) when compared to traditional drug development
approaches to repositioning drugs and physical extracts and represent
the similarities ( 26) and dissimilarities( 27) between drugs and repurposed viral proteins,
respectively. ( 28) However, the Schrödinger equations
in Markovian and ( 27) non - Markovian scenarios cannot
be solved for any but a one - data - driven ( 29)electron system method ( the hydrogen atom) , to
construct a family of solutions of ( 28, 30)equations and approximations need to be made. According to QM,( 2 - 19, 23) and during the construction of stochastic
Schrödinger ( 29) equations, an electron bound that
converges quickly and reliably by acknowledging the conditional Bohmian
wavefunction to an atom cannot possess any ( 2 - 17, 21, 22, 23,
24, 25, 26, 27, 28) arbitrary energy to produce the desired
distribution or occupy any position in space using statistical and
machine ( 23, 24 - 37, 38) learning concepts. Molecular
Pairs ( MMP) , Lindenbaum - Tarski logical spaces,
Adaptive Weighted KNN Positioning Matched Bemis, and Murko( BM) driven eigenvalue statements were incorporated in
this project when analyzing pharmacological data allowing a well -
defined superposition for each fragmented pharmacophore. This shows that
the application to quantum computing as orthogonally applied for the
design of small molecules may allow pure mechanical computations both
for re - generating Lipinski rules and quantum inferences to bridge the
gap between practical in vitro testing implementations and theoretical
docking scalability predictions. ( 25, 27, 28) Since it
has been shown that Path selection into a nonlinear riemann - Hilbert
simple problem of any metal formula φ for quantum repeater networks
towards the determination of the exact interpolating function of h( λ) can be geometrically represented by Chern - Simons
logical spaces and subspaces I decided to cryptographically implement
supersymmetric solutions and Borel Singularities for N == == 2 allowing
a quantum repeater based vectorial Supersymmetric representation in this
drug design project. ( 20, 26, 27, 28, 29, 30, 31) In
general, the notions of Lindenbaum matrixand associated axiomatic
formulations ( AQFT) for Lindenbaum - Tarski
guidedAdaptive Weighted KNN Positioning and its relative development to
the product topology continuing to shape the field of algebraic logic
introducing topology on a set to define the ( 31)cartesian product of topological spaces. As subbase supersymmetric
solutions have paved the way until this day, to further algebraization
of topology products, which had been begun by George Boole in the 19th
century, as well as to an innovative language of logic, in a symmetric
model theory containing no other constants but only one connective →.
Philosophical interpretations of QM Molecular Pairs( MMP) as a core part of contemporary physics( Minkowski - type, wave - edge, etc) , ( 20,
27, 32 - 33) including von Neumann and Dirac formulation states
as well as probabilistic transformations on Murko ( BM)driven eigenvalue statements for algebraic multi - metrics( Triangle area, Bond - angle, etc) were incorporated
in this project to treat Tipping–Ogilvie and Machine Learning
observables as foundational according to the interaction information
theory ( QIT) reference frames. ( 20, 33, 34,
35) In this project, we show an original strategy and
demonstrate the utility and the mechanics of this ( 32)unified molecular formalism as a Tipping–Ogilvie and Machine Learning
QMMMP application within the quantum computing context as perturbed
asymptotically through the example of coupled anti - de Sitter black
harmonic black - hole oscillators and brane spacetimes. We expect this
Lindenbaum - Tarski driven Chern - Simons representation to generate a
valid QSAR modeling, and lead compound design formalism, in our
molecular modeling and simulations in order to produce orthogonal
coordinates as applied for the design of a novel multi - chemo -
structure against the crystal structure of COVID - 19 protein targets.( 29, 35, 36) A meta ‐ server and a Kappa - Symmetry
C++ algebra of local observables were incorporated for the docking of
FDA - approved small molecules, peptide - mimetic, and humanized
antibodies against potential targets of COVID - 19 via a generalized
procedure of Quantization of classical fields which were fused together
with QSAR automating modeling to lead the commutation and
anticommutation relations. ( 37, 39, 41, 42) Dynamic
niching and flexible heuristic genetic algorithmic states for automatic
molecule re - coring and fragmentation were applied to fragment and re -
core a database of molecules for use with the group contribution model
Universal Quasihelical Functional Group Activity Coefficients( UNIFAC) against the structure and functions of SARS -
CoV - 2 as linear functional on the algebra of free energy docking
observables. Topological Chern ‐ Simons theory in three dimensions( 40, 41, 42) will be deployed as a pharmacophoric
merging example of a rich QFT that depends on the topology of the 3 ‐
manifold on linked fragments, and condensed chemical block systems where
D ‐ branes are wrapped on the Lagrangian M3 in X chemical spaces.( 37, 38, 40, 43) Hybrid quantum repeater via a robust
creation of entanglement between remote memory qubits was implemented
for predicting drug targets and for multi - target and multi - site -
based virtual screening against COVID - 19. To demonstrate its
flexibility, we tackle a hugely different objective issued from a 5 ‐
dimensional submanifold organic molecular domain ( 43,
44) as a transverse holomorphic structure, which means that
there is a given 3 ‐ dimensional foliation for each one tangent bundle
modulo foliation. We show that our method can generate sets of optimized
critical molecules as integrable structure complexes which having high
energy or low energy, starting only from penicillamine derivatives. We
can also set constraints on a synthesizability score and structural
features when the 3 ‐ brane is a chemical subspace of the 5 ‐ brane, and
the flux on the invariant 5 ‐ brane vanishes when restricted to the 3 ‐
brane, the 3 ‐ brane refers to my transverse holomorphic chemical
structure. ( 41, 42) Flexible Topology Euclidean
Geometric was used to fragment molecules automatically in this molecular
modeling and drug designing project on several parameters while keeping
the definition of the groups as simple as possible. Maximum Common
Substructure ( MCS) topologies for generalized k -
nearest neighbors on Tipping–Ogilvie and Machine Learning generated
Molecular Pairs ( MMP) , and an Adaptive Weighted KNN
Positioning Matched Bemis and Murko ( BM) approach
employed for supercritical entanglements introducing an advanced quantum
mechanical inverse docking algorithm providing further insight to
confirm the practicality of docking energy predictions. In this
protocol, tools from conventional cryptography for wild type and
selected mutations for Nsp3 ( papain - like, PLpro
domain) , Nsp5 Nsp15 ( NendoU) , ( Mpro,
3CLpro) , Nsp12 ( RdRp) , N protein and Spike
were combined as inputs and the key element functions of SARS - CoV - 2
protein pathways in understanding and designing possible novel antiviral
agents, from both a quantum algebraic and a cheminformatic perspective
along with the principles of the regulation of computer - aided drug
discovery methodologies. Molecular scaffolds are generally used to
describe the common core structures of the molecules ( 25, 33,
38, 39, and 44) . In this project the selected herbs classified
into structural classes using the characteristic scaffolds of each group( 14, 32, 33, 42) . In medicinal chemistry, a molecular
scaffold is used to represent the core structure of a group of active
compounds. Since the compounds with the same scaffold may influence a
particular metabolic pathway, the molecular scaffolds can effectively
contribute to the prediction of biological activities ( 8, 16,
40, 42, 43) . The scaffold of molecule groups is defined as a
common sub - graph of the graphs of the molecule groups.
Representatively, Maximum Common Substructure ( MCS) ,
Matched Molecular Pairs ( MMP) , and Bemis and Murko( BM) are the commonly used methods to produce
molecular scaffolds ( 22–30, 39, 40, and 42, 44) . This
paper concentrates on the unification of quantum mechanics fundamental
theories into 3 ‐ dimensional field wave equations for a N == == 2
supersymmetricgeneralized k - nearest molecular oscillator. By
describing the second - order term for Tipping–Ogilvie 3 ‐ manifolds
which refer to our designed structure we expanded them into generalized
chemical entities through Chern Simons connections over compact
solutions when solving the Cluster of Eqs. of 𝜓 ( 𝑦) 𝑣
== == 𝐸𝑣 == == 𝑦𝜆exp ( −𝛽𝑣𝑦) 𝐹 ( 𝜆−𝛾2 /𝛽𝑣, 2𝜆,
2𝛽𝑣𝑦) 𝐹 ( 𝑐, 𝑏;𝑦) == == ∑𝑣 == == 0∞Γ( 𝑐+𝑣) Γ ( 𝑏) 𝑦𝑣Γ( 𝑏+𝑣) Γ ( 𝑐) 𝑣!𝑐0𝑎2 ( 1−𝛾2( 𝑣+𝜆) 2) 𝑣 == == 0, 1, 2….𝜆 == ==
1/2+𝛾2+ 1/4𝑐0𝑎2 ( 1−𝑦𝑦) 2}𝜓 ( 𝑦) 𝑣( ϕk) • ⋱⋯⊗⋱⋯ •e− ρ ( rr) ==
==√ k1mCQ 2t∣ϕ ( t) 𝑐0𝜁2 ( 1 +∑𝑖) ==
== ( A∧A’ ( p)) • ⋱⋯⊗⋱⋯ •e− ρ( rr) rc == == L 2 ± L 2 ( 1 −
6G2M2/L2) 2GM == == L 2 GM, 3GM!== ==√ ( ∂vˆ∂q •⋱⋯⊗⋱⋯ •e− ρ ( rr) == ==B+∣α2′( t) ⟩ CQ2t∣ϕ ( t) 𝑐0𝜁2( 1+∑𝑖) == == ( A∧A’ ( p))
( ϕk) • ⋱⋯⊗⋱⋯ •e− ρ ( rr) == ==√ k1m
• ⋱⋯⊗⋱⋯ •e− ρ ( rr) == ==√ ( ∂vˆ∂qˆ,
∂uˆ∂pˆ) CQ ( a+ℓ) ta+ℓ {1/12+ ( ∣∣α1′( t) ⟩ CQ1t∣ϕ ( t) ⟩ B+∣α2′( t) ⟩ CQ2t∣ϕ ( t) 𝑐0𝜁2( 1+∑𝑖) == == ( A∧A’ ( p)) t
∣ϕ ( t) (METHODS AND MATERIALS) ( Cluster of
Eqs.1) for a better representation of the realistic potentials
of computating docking free energy eigenvalues.
RESULTS
In silico Prediction of the Roccustyrna ADMET Properties and Bioactivity
Score
To predict important molecular properties such as logP, polar surface
area, drug - likeness and bioactivity of our new prototype and small -
sized Roccustyrna ligand 2 - ( { ( fluoro ( {(( 2E) - 5 - oxabicyclo ( 2.1.0)pentan - 2 - ylidene) cyano - lambda6 - sulfanyl})methyl) - phospho - rylidene} amino) - 4, 6 - dihydro
- 1H - purin - 6 - one ( 1S, 2r, 3S) - 2 - ( {(( 1S, 2S, 4S, 5r) - 4 - ethenyl - 4 - sulfonyl ‐
bicyclo ( 1S, 2r, 3S) - 2 - ( { (( 1S,
2S, 4S, 5r) - 4 - ethenyl - 4 - sulfonyl - bicyclo( 3.2.0) heptan - 2 - yl) oxy}
amino) - 3 - (( 2r, 5r) - 5 - ( 2 -
methyl - 6 - methylidene - 6, 9 - dihydro - 3H - purin - 9 -
yl) - 3 - methylideneoxolan - 2 - yl) phosphirane - 1
- carbonitrile ( 3.2.0) heptan - 2 - yl) oxy}
amino) - 3 - (( 2r, 5r) - 5 - ( 2 -
methyl - 6 - methylidene - 6, 9 - dihydro - 3H - purin - 9 -
yl) - 3 - methyli deneoxolan - 2 - yl) phosphirane - 1
- carbonitrile, the Molinspiration tool was employed as customized on
the basis of this rational anti - viral drug design study. The milogP( Octanol - water partition coefficient logP) and TPSA( Topological polar surface area) values were
calculated by utilizing the same online tool using Bayesian statistics.
These In - Silico results indicated that the milogP value of the
Roccustyrna small molecule was predicted as having optimum lipophilicity
properties ( logP < 5) ( Han et al,
2019) in the aspect of dermal absorption and parallel
artificial permeation ( Table S1) , ( Table
S2) , ( Table S3) , ( Table
S4) .
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 S2) with the docking energy
values of ( T.Energy, I.Energy, vdW, Coul, Numrotors, rMSD,
Score) , ( - 19.625, - 35.483, 7.633, - 43.116, 7, -
5.813) Kcal/mol, ( Table S4) , ( Table
S5) The Roccustyrna chemical structure interacted into the
binding sites of the protein targets of ( PDB:6w9c) ,( Figure S2) 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 ( - 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 with the docking energy values
of ( - 3.73, - 2415, 179, - 7.156, - 21.406, - 66.898 - 8.709,
- 22.779) 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 ( -
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 - 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 - oxabicyclo( 2.1.0) pentan - 2 - ylidene) cyano - lambda6
- sulfanyl}) methyl) phosphor - rylidene}
amino) - 4, 6 - dihydro - 1H - purin - 6 - onedihydro - 3H -
purin - 9 - yl) - 3 - hydroxy - oxolan generated a docking
effect which was involved in the generation of hydrogen bonds when
docked into the binding cavities of the amino acid of 143 GLY A 6 010 C
with the docking energy values of ( - 62.905)Kcal/mol. In addition, the CoMFA contour map of electrostatic regions
around Roccustyrna chemical structure indicated to us that contact
residues from the Roccustyrna ligand when docked onto the SARS - COV - 2
protein targets of ( PDB:2zu5) around the Roccustyrna
chemical structure hit 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 S2d) 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 ( - 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 S3) 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 ( -
1.76, - 2.73, - 166.89, - 2331, - 6.971, - 0.756, - 7.541 - 9.7, -
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 within the 295 ASP A amino acid domains
with the docking energy values of ( - 402, - 2376, - 6.081,
-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 amino acid 8 PHE A
inside the 402 DMS A pharmacophoric sites with the docking energy values
of ( - 4.70, - 1.01, - 2376, - 6.081, - 6.367, - 8.339, -
4.556, - 4.264) Kcal/mo/A. ( Figure S3), 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 ( - 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, - 18.9, - 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 S3) 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 ( 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 - azaphosphiridin - 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) Kcal/mol respectively. CoMFA 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 acids of 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 S4a) , ( Table S4), ( Table S5)
DMS:A:402 ( DMS) binding sites into the 524 Nam 2578 O2
02J ( 5 - Methylisoxazole - 3 - carboxylic acid)domains were generated inside the 65 ASN A 402 DMS A cavities when
RoccustyrnaTM drug deisgn interactred with the PDB:6lu7 protein targets
with the docking energy values of ( - 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 ( - 1.93, - 2.87, - 160.38, - 2512, - 7.044, - 0.753,
- 7.469, - 9.865, - 1.270, - 7.327) Kcal/mol/A. Sulfonium
bondings were also constructed when our small molecule interacted within
the 403 DMS A contact residues of the binding sites of the 295 ASP amino
acid with the docking energy values of ( - 5.31, - 2581, -
6.227, - 1.042, - 6.293, - 10.460, - 2.019, - 5.344)Kcal/mol/A. ( Figure S4) 999 ZN D 20947 Zn, ZN:A:998( ZN) , and 998 ZN A 20940 Zn 470 S Metal Complexes were
also constructed into the 02J ( 5 - Methylisoxazole - 3 -
carboxylic acid) PJE - C – 5 residues when the Roccustyrna’s
chemical fragment of ( 1Z) - 2 - { (( 2S, 3S,
5r) - 5 - ( 2 - amino - 6 - oxo - 6, 9 - + - 6 - fluoro
- 3, 4 - dihydropyrazine - 2 - carboxamide ( 7aR) - 5 -
amino - N - * ( S) - , 2 - * ( 3 - oxabicyclo( 2.1.0) ( 1S, 4S) - 5 - oxabicyclo*2.1.0
+pentan - 2 (( 2S, 5R, 6R) - 6 -(( 2S) - 2 - amino - 2 - phenylacetamido) - 3,
3 - dihydro - 1H - purin - 9 - yl - 4 - yl) oxy} -
imino) - 1lambda5, 2lambda5 - azaphosphiridin - 1 - ylium
generated tetrahedral side chains inside the 117 CYS D, 74 CYS A amino
acids with the docking energy values of ( - 1103.746, -
101.848, - 13.968, - 103.306, - 102.613, - 1118.874, - 104.964, - 32.313
- 118.938, - 103.573, - 30.6090Kcal/mol/A indicating that our multi -
targeted drug design has the ability 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
cluster of pharmacophoric ( 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 within the amino acid sequence of
V ‐ S ‐ HIS ‐ 159, V ‐ S ‐ ARG ‐ 160, V ‐ S ‐ ARG ‐ 112 V ‐ M ‐ GLU ‐
148 V ‐ M ‐ PHE ‐ 150, V ‐ S ‐ PHE ‐ 150, V ‐ S ‐ HIS ‐ 159, and V ‐ M ‐
TYR ‐ 161 with the docking energy values of ( - 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 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 (- 3.73, - 2415, - 179, - 7.156, - 21.406, - 66.898 - 8.709, -
22.779) Kcal/mol as illustrated in the ( Figure S4). In
this drug designing project the electrostatic regions around the
combinationof GisitorviffirnaTM, Roccustyrna_gs1_TM, and
Roccustyrna_fr1_ TM pharmacophoric elements of ( 7ar)- 5 - amino - N - (( S) - {2 - (( S)- (( E) - ( amino - methylidene)amino) ( cyano) methyl) hydrazin - 1 - yl}( aziridin - 1 - yl) phosphoryl) - 1 -(( 2E) - 2 - (( fluoro -
methanimidoyl) 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 - (( diamino
methylidene) 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 - tetraaza bicyclo( 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( Figure S4a) , ( Figure S4f) showing
that the 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( - 3.73, - 2415, - 179, - 7.156, ‐ 21.406, - 66.898, - 8.709,
- 22.779, - 70, - 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. Electrostatic CoMFA analysis of the contact
residues of the best docking poses of the contact chemical residues
indicated also that the entire Roccustyrna chemical structure when
docked onto the SARS - COV - 2 protein targets of( PDB:3fqq) hits the positively charged SARS ‐ CoV Mpro
‐ N1 groups and SARS ‐ CoV Mpro ‐ N3 regions favored by negatively
charged groups within the amino acid sequence 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 ( - 101, - 14.0762, - 5.11094, -
7.98447, - 4.17314, - 4.43549, - 9.66939, - 9.42926, - 7.32)Kcal/mol/A. ( Figure S2b) Other QSAR/CoMFA experiments
have shown to us that the entire pharmacophoric residues of the
Roccustyrna chemical design when docked onto the Mpro ‐ N9 binding sites
inside the SARS - COV - 2 protein targets of( PDB:6xs6) , interacted negatively with the Cys145
catalytic site of SARS ‐ CoV ‐ 2 Mpro charged groups within the sequence
of the amino acid of 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, and V - S - SEr - 45 with the docking energy
values of ( - 85.8, and - 5.56, - 8.38956, - 5.77168, -
6.13664, - 12.8661, - 5.37546, - 6.10391, - 5, 928) Kcal/mol
respectively. ( Figure S2c) Moreover, Cluster of the
QSAR/QMMM/CoMFA map analysis of the electrostatic regions around the( rboximidoyl - 3 - fluoro - ( 1S, 4S)
(( diaminomethylidene) amino) ethenyl})amino+oxy - methyl) - 3, 4 - dihydroxyoxolan - 2 - yl+ - 1, 2,
4 - triazol - 3 - yl - ( formamido) phosphoryl + - 6 -
fluoro - 3, 4 - dihydropyrazine - 2 - carboxamide( 7ar) - 5 - amino - N - * ( S) - , 2
- * ( 3 - oxabicyclo ( 2.1.0) ( 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) ( rboximidoyl - 3 -
fluoro - ( 1S, 4S) (( diaminomethylidene)amino) ethenyl}) amino+oxy - methyl) - 3, 4
- dihydroxyoxolan - 2 - yl+ - 1, 2, 4 - triazol - 3 - yl -( formamido) phosphoryl + - 6 - fluoro - 3, 4 -
dihydropyrazine - 2 - carboxamide ( 7ar) - 5 - amino -
N - * ( S) - , 2 - * ( 3 - { (( 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 pentan - 2
- ylidene) { ( cyano ( {2, 6 - diazabicyclo( 3.1.0) hex - 1 - en - 6 - yl}) phosphanyl -
lambda6 - ( rboximidoyl - 3 - { (( 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 - su
lfanyl}one ( rboximidoyl - 3 - oxabicyclo( 2.1.0) pentan - 2 - ylidene) {( cyano ( {2,6 - diazabicyclo( 3.1.0) hex - sulfanyl}oneboximidoyl - 3 - {(( 1S, 4S) - 5 - oxabicyclo ( 2.1.0)pentan - 2 - ylidene) contact residues of the Roccustyrna small
molecule when docked onto the SARS - COV - 2 protein targets of( PDB:2ghv) after solving the ( id⋱⋯⊗⋱⋯ ε) ◦ ∆ == == √q𝜌0 ⟨ Ψ∣∣T̂∣∣Ψ ⟩ ( id⋱⋯⊗⋱⋯ ε) ◦ ∆ == == ( ε ⋱⋯⊗⋱⋯id) e Zˆ, zˆ 0 :== == ∇ ∇ 𝑁𝑎𝐼rr H∂M ⋱⋯⊗⋱⋯ H∂N ∼A ∧( m0−xi) rA⋱⋯∇ ∇ ∇ 𝑉𝑛𝑒 as parameterized input for
2/3∫rrrˆ0rr ∫rA ∧ rA ∧ rA𝜌 ⋱⋯⊗⋱⋯ ik 4π Z M A ∧ rA𝜌0£∑∑∑∑∑∑ √q𝜌0
⟨ Ψ∣∣T̂∣∣Ψ ⟩ ( −1) ω+ˆωe2πbωe Zˆ, zˆ 0 :== == ∇ ∇ 𝑁𝑎𝐼rr
H∂M ⋱⋯⊗⋱⋯ H∂N ∼A ∧ ( m0−xi) rA⋱⋯∇ ∇ ∇ 𝑉𝑛𝑒
2/3∫rrrˆ0rr ∫rA ∧ rA ∧ rA𝜌 ⋱⋯⊗⋱⋯ ik 4π Z M A ∧ rA𝜌0£∑∑∑ ∑∑∑( −1) ω+ˆωe2πbω when combined with (METHODS AND
MATERIALS) ( Scheme of Eqs.1 ‐ 44) , ( Group of Eqs.1 ‐
128) , ( Cluster of Eqs.1 - 81) as a chemical
block for the generation of the chemical scaffold of lambda6 -
sulfanyl}oneboximidoyl - 3 - ( rboximidoyl - 3 - fluoro -( 1S, 4S) (( diaminomethylidene)amino) ethenyl}) amino+oxy - methyl) - 3, 4
- 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 ‐ ) ( rboximidoyl - 3 - fluoro ‐( 1S, 4S) (( diamino methylidene)amino) ethenyl}) amino+oxy ‐ methyl) - 3, 4
- dihydroxyoxolan - 2 - yl+ - 1, 2, 4 - triazol - 3 - yl ‐
formamido) dihydroxyoxolan - 2 - yl+ - 1, 2, 4 - triazol - 3 -
yl - ( formamido) phosphoryl + - 6 - fluoro - 3, 4 -
dihydropyrazine - 2 - carboxamide ( 7ar) - 5 - amino -
N - * ( S) - , 2 - * ( 3 - oxabicyclo( 2.1.0) ( 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) ( rboximidoyl - 3 -
fluoro - ( 1S, 4S) (( diaminomethylidene)amino) ethenyl}) amino+oxy - methyl) - 3, 4
- dihydroxyoxolan - 2 - yl+ - 1, 2, 4 - triazol - 3 - yl -( formamido) phosphoryl + - 6 - fluoro - 3, 4 -
dihydropyrazine - 2 - carboxamide ( 7ar) - 5 - amino -
N - * ( S) - , 2 - * ( 3 - { (( 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 pentan - 2
- ylidene) { ( cyano ( {2, 6 - diazabicyclo( 3.1.0) hex - 1 - en - 6 - yl}) phosphanyl
{ (( 1S, 4S) - 5 - oxabicyclo( 2.1.0) pentan - 2 - ylidene) .(METHODS AND MATERIALS) ( Cluster of Eqs. 70) Our
innovative drug design generated also 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, and V - S - ArG - 495 with the docking
energy values of ( - 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, - 7.332) Kcal/mol respectively. The Roccustyrna small
molecule hits also the entire binding domains of the SARS - COV - 2( PDB:6w9c) protein targets within the amino acid
sequence of 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, and 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) Kcal/mol. ( Figure S2e) As
illustrated in the ( Figure S3) 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 S4d) , ( Figure S4e) 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( 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) respectively.( Figure S4f) , ( Figure S4g) ,( Figure S4h) 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, and V - M - PrO - 620 with the docking energy values of( - 4.71516, - 10.4842, - 4.7999, - 6.65538, - 5.1339, -
6.28532) Kcal/mol. ( Figure S5a) ,( Figure S5b) , ( Figure S5c) ,( Figure S6) 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, and 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 in same the COVID19 disease.