Abstract

p38a is a significant target for drug designing against cancer. The overproduction of p38a MAPK promotes tumorigenesis inhead and neck squamous cell carcinoma (HNSCC). The ATP binding and an allosteric site referred as DFG are the key sites ofthe p38a mitogen activated protein kinase (MAPK) exploited for the design of inhibitors. The p38 mitogen-activated protein kinase (MAPK) is a signaling intermediate downstream of proinflammatory cytokine receptors released following environmental stress. This kinase is known to play an important role in inflammatory and autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Here, we present for the first time a novel drug-target combined Bayesian formulation for the Rational Discovery of a Specific FWCS/LQIHFTLIXAFCCEN Peptide mimetic Pharmacophoric Inhibitor against p38a MAPK at Allosteric-Sites-HNSCC. A Therapeutic Modality forHNSCC using Predicting drug–target interactions from chemical and genomic kernels by Bayesian matrix factorization. This paper discusses quantum mechanical schemas for describing waves with non-abelian phases, Fock spaces of annihilation-creation operators for these structures, and the Feynman recipe for obtaining descriptions of particle interactions with external novel drug-target fields combined to Bayesian formulation for the Rational Discovery of a Specific FWCS/LQIHFTLIXAFCCEN Peptide mimetic Pharmacophoric Inhibitor against p38a MAPK at HNSCC Allosteric-Sites on Hypercomplex based Extensions of Quantum Theory.

Keywords

novel; drug-target;combined; Bayesian formulation;Rational Discovery; FWCS/LQIHFTLIXAFCCEN;Peptide mimetic;Pharmacophoric Inhibitor;p38a MAPK; Allosteric-Sites;HNSCC; A novel drug-target combined Bayesian formulation for the Rational Discovery of a Specific; Hypercomplex Extensions; Quantum Theory; novel drug-target; Bayesian formulation; Allosteric-Sites; Composition Algebras; Hilbert Spaces; Fock Spaces; Non-Abelian Gauge Fields;

Abstract

Using von Neumann’s continuous geometry in conjunction with A. Connes’ noncommutative geometry an exact mathematical-topological picture of quantum spacetime is developed ab initio. The final result coincides with the general conclusion of E-infinity theory and previous results obtained in the realm of high energy physics. In particular it is concluded that the quantum particle and the quantum wave spans quantum spacetime and conversely quantum particles and waves mutates from quantum spacetime of a novel drug-target combined Bayesian formulation for the Rational Discovery of a Specific FWCS/LQIHFTLIXAFCCEN Peptide mimetic Pharmacophoric Inhibitor against p38a MAPK at HNSCC Allosteric-Sites.

Keywords

E-Infinity, Quantum Spacetime, Noncommutative Geometry, Fractals, Transfinite Set Theory, Von Neumann Continuous Geometry, Cantor Sets, Fusion Algebra, Zero Point Energy, Vacuum Fluctuation, Quantum Field Theory, Casimir Effect, Dark Energy, Exact Mathematical Picture; Quantum Spacetime;Hypercomplex Extensions; Quantum Theory; novel drug-target; combined Bayesian formulation; Rational Discovery; FWCS/LQIHFTLIXAFCCEN; Peptide mimetic; Pharmacophoric Inhibitor; p38a MAPK; HNSCC Allosteric-Sites;

Abstract

In previous scientific efforts random peptide libraries containing millions of 90 Mm TentaGel beads, each withits own unique ovarian cancer disease associated amino acid sequence were generated by using ‘‘one-bead one-compound’’ combinatorial chemistry tchnology. A cyclic random 8-mer library was screened with CAOV-3 (a human ovarian adenocarcinoma cell line) and beads with a unique ligandthat bind to the cell surface receptors were coated byone or more layers of cells. These positive beads were isolated, stripped, and microsequenced. Several peptidemotifs were identified from these screenings, some of which were novel and unique, e.g., cDGX4GX6X7c. Structure-activity relationship studies of this peptiderevealed that the L-aspartate residue at position 2, thetwo glycines at positions 3 and 5, and the two Dcysteinesat the amino and COOH terminus are critical foractivity. Here, in Biogenea we have for the first time in silico discovered novel targeting peptide chemical pharmacophore for human ovarian cancer highly expressed mRNAs fro ‘‘one-bead one-compound’’combinatorial libraries.

Keywords

hydrophobic; residue;computer-aided; discovery;novel targeting; peptide;chemical; pharmacophore;human ovarian cancer; highly expressed; mRNAs, ‘‘one-bead one-compound’’combinatorial libraries;

Abstract

The existence of any elementary particle in universe requires the existence of some region of universe occupied by it. By taking the volume of this occupied region, the author will reformulate the relativistic quantum field theory using new 3-dimensional region-like idealization of elementary particles and hereinafter will call the total volume of all regions occupied by the elementary constituent particles of the quantum system the occupied volume. Also the author will call the set of all regions of universe filled by elementary constituent particles of the quantum system the occupied path. Always any quantum system is existed at a head of its occupied path. This path is growing by mutual filling and leaving regions of universe by its elementary constituent particles. The conservation of this elementary constituent particle requires the conservation of its occupied volume during this process. This requirement could be summarized by the following conditions: 1) the total volume of all regions of universe filled by the elementary constituent particles of the quantum system minus the total volume of all regions of universe left by these elementary constituent particles must be equal to the occupied volume of the quantum system; 2) the total increase in the occupied volume of the quantum system due to the absorption of another elementary particles from outside its occupied regions minus the total decreasing in its occupied volume due to the emission of another elementary particles outside its occupied regions must be equal to the occupied volume of it. The wave-particle duality of the elementary constituent particles implied accumulation of them as the finite set of interfered waves. This accumulation of elementary constituent particles causes the absolute probabilistic nature of event of finding the elementary consistent particle in specified interfered wave, and hence the mathematical representation of this interfered wave should take into account the value of probability amplitude of finding an elementary particle inside the region occupied specified interfered wave. In quantum theory this probability amplitude corresponds to complex amplitude of the wave function of interfered wave. Also in Hilbert’s representation of the quantum theory these wave functions are representing the components of the quantum state vector. In this paper the author will develop the transformation theory of the region-like quantum state of the quantum system. In this study, we managed to reformulate of the Relativistic Quantum Field Theory using Region-Like Idealization of the Elementary Particle Identification of an one-bead by one-compound computer-aided discovery novel peptide mimetic pharmacophore against human ovarian cancer highly expressed on conserved mRNAs-cDGX4GX6X7c associated combinatorial libraries.

Keywords

Reformulation; Relativistic Quantum Field Theory; Region-Like Idealization; Elementary Particle Identification; one-bead by one-compound; computer-aided discovery; novel peptide mimetic; pharmacophore; human ovarian cancer; highly expressed; fconserved; mRNAs-cDGX4GX6X7c; combinatorial libraries; Creation, Annihilation, Animation, Occupied Volume, Occupied Path,

Abstract

BACE-1 is the β-secretase responsible for the initial amyloidogenesis in Alzheimer’s disease, catalyzing hydrolytic cleavage of substrate in a pH-sensitive manner. The catalytic mechanism of BACE-1 requires water-mediated proton transfer from aspartyl dyad to the substrate, as well as structural flexibility in the flap region. Thus, the coupling of protonation and conformational equilibria is essential to a full in silico characterization of BACE-1. In this work, we perform constant pH replica exchange molecular dynamics simulations on both apo BACE-1 and five BACE-1-inhibitor complexes to examine the effect of pH on dynamics and inhibitor binding properties of BACE-1. In our simulations, we find that solution pH controls the conformational flexibility of apo BACE-1, whereas bound inhibitors largely limit the motions of the holo enzyme at all levels of pH. The microscopic pKa values of titratable residues in BACE-1 including its aspartyl dyad are computed and compared between apo and inhibitor-bound states. Changes in protonation between the apo and holo forms suggest a thermodynamic linkage between binding of inhibitors and protons localized at the dyad. Utilizing our recently developed computational protocol applying the binding polynomial formalism to the constant pH molecular dynamics (CpHMD) framework, we are able to obtain the pH-dependent binding free energy profiles for various BACE-1-inhibitor complexes. Our results highlight the importance of correctly addressing the binding-induced protonation changes in protein-ligand systems where binding accompanies a net proton transfer. This work comprises the first application of our CpHMD-based free energy computational method to protein-ligand complexes and illustrates the value of CpHMD as an all-purpose tool for obtaining pH-dependent dynamics and binding free energies of biological systems.In silico designed of an Anticancer Peptide SVS-1 multipharmacophore as a potential drug-like efficator in Preceding Membrane Neutralization using a web server multi-mimotopic algorithmic approach for biclustering analysis of expression data.Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria. Anticancer peptides (ACPs) are polycationic amphiphiles capable of preferentially killing a widespectrum of cancer cells relative to non-cancerous cells. Their primary mode of action is aninteraction with the cell membrane and subsequent activation of lytic effects, however it remainscontroversial the exact mechanism responsible for this mode of action. It has in previous studies been shown that utilizing zeta potential analyses it was possible to demonstrate the interaction of a small anticancer peptide with membrane modelsystems and cancer cells. Electrostatic interactions have a pivotal role in the cell killing processand in contrast to the AMPs action cell death occurs without achieving full neutralization of themembrane charge. Formation of insoluble amyloid plaques in the vascular and hippocampal areas of the brain characterizes Alzheimer’s disease, a devastating neurodegenerative disorder causing dementia. Site-specific hydrolytic catalysis of β-secretase, or BACE-1, is responsible for production of oligomerative amyloid β-peptide. As the catalytic activity of BACE-1 is pH-dependent and its structural dynamics are intrinsic to the catalysis, we examine the dependence of dynamics of BACE-1 on solution pH and its implications on the catalytic mechanism of BACE-1. Also, we highlight the importance of accurate description of protonation states of the titratable groups in computer-aided drug discovery targeting BACE-1. We hope the understanding of pH dependence of the dynamics and inhibitor binding properties of BACE-1 will aid the structure-based inhibitor design efforts against Alzheimer’s disease.In silico designed of an Anticancer Peptide SVS-1 multipharmacophore as a potential drug-like efficator in Preceding Membrane Neutralization using a web server multi-mimotopic algorithmic approach for biclustering analysis of expression data.Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria. The advent of microarray technology has revolutionized the search for genes that are differentially expressed across a range of cell types or experimental conditions. Traditional clustering methods, such as hierarchical clustering, are often difficult to deploy effectively since genes rarely exhibit similar expression pattern across a wide range of conditions. Web-enabled service called GEMS (Gene Expression Mining Server) for biclustering microarray data where Users may upload expression data and specify a set of criteria. In this study GEMS performs bicluster mining based on a Gibbs sampling paradigm of Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria to the in silico design of an Anticancer Peptide SVS-1 multipharmacophore as a potential drug-like efficator in Preceding Membrane Neutralization using a multi-mimotopic algorithmic approach for biclustering analysis of expression data.. Here, in Biogenea we have for the first time discovered an Anticancer Peptide SVS-1 multipharmacophore with an ini silico evaluated Efficacy in Preceding Membrane Neutralization using a web server for biclustering analysis of expression data.

Keywords

In silico designed; Anticancer Peptide; SVS-1; multipharmacophore; potential; drug-like; efficator; Preceding Membrane; Neutralization; multi-mimotopic; algorithmic approach; biclustering analysis; expression data; Conformational Dynamics; Binding Free Energies; Inhibitors; BACE-1; Protonation Equilibria;

Abstract

Human T lymphotropic virus type 1 (HTLV-1) was the first isolated retrovirus and is the causative agent of Adult T cell leukemia or Tropical Spastic Paraparesis which develops in 6-10 % of HTLV-1 positive individuals. Viral transmission takes place vertically or horizontally via cell to cell contact and syncitia formation between infected and non-infected cells. The viral envelope is responsible for the attachment and entry of the virus into the host cell. Env is composed of two subunits: referred to as the surface subunit, and the gp21 transmembranous subunit. It has been proposed that gp46 is mainly involved in host cell receptor binding and gp21 is involved in post binding events resulting in the fusion of host cell membrane with the infected cell membrane. There has been no effective cure against HTLV-1 and it is resistant to conventional means. We explore the viability of using intrinsically quantum phenomena for molecular sensing. We formulate a theory for coherent sensing by combining the full analytical description of electronic relaxation processes with mass diffusion and charge transport models. This theory produces molecular-scale design criteria for sensors with responses rooted in quantum mechanical coherence phenomena. For example, the sensitivity of the detector can increase with decreased coupling between the molecular binding sites and the sensor substrate. Exploiting quantum properties of the analyte and the sensing element (e.g., electronic affinity, polarizability, etc.) enables enhanced discrimination among multiple analytes. Discovery and a computerized quantitative bio-informatic in silico Development of a Synthetic Gp 46-gp21 derived P400-P197 Peptide mimetic pharmacophore as a potential HTLV-1 Fusion Inhibitor in a mass-action law based new cluster of algorithmsSensing of molecules using quantum dynamics.Therefore investigations in possible therapeutic approaches are very important. One possible therapeutic strategy against HTLV-1 is the use of peptide fusion inhibitors to prevent transmission of the virus. Here, in Biogenea we have for the first time focused on HTVS programs with graphical user interfaces (GUIs) that use either DOCK or AutoDock for the prediction of DockoMatic, PyRx, DockingServer, and MOLA since their utility has been proven by the research community, they are free or affordable, and the programs operate on a range of median-effect equation of the massaction law deduced from over 300 mechanism specific-equations which has been shown to be the unified theory that serves as the common-link for complicated biomedical systems in a computer platform for the in silico discovered Synthetic Peptide mimetic multi-targeted pharmacophore as a novel Potential HTLV-1 Fusion Inhibitor Therapeutics using a mass-action law based algorithm for cost-effective approach for cancer drug discovery and development.

Keywords

Sensing of molecules; quantum dynamics, Discovery, computerized, quantitative bio-informatic, in silico, Development, Synthetic, Gp 46-gp21, derived P400-P197, Peptide mimetic, pharmacophore, HTLV-1, Fusion Inhibitor, mass-action law, new cluster of algorithms.

Abstract

Quantum key distribution is a technique to securely distribute a bit string between two parties by using the laws of quantum mechanics. The security of this technique depends on the basis of quantum mechanics rather than the difficulty of the mathematical calculation as in the classical encoding. Researches in this field have shown that the quantum key distribution will be fully func-tioning outside the laboratory in a few years. Due to the complexity and the high efficiency of the device, the verification is needed. In this article, we use PRISM to verify the security of the quan-tum key distribution protocol, which uses the entangled photon based on BB84 in silico Model Checking Development of a Synthetic Gp 46-gp21 derived P400-P197 Peptide mimetic pharmacophore as a potential HTLV-1 Fusion Inhibitor in a mass-action law based new cluster of algorithms protocol

Keywords

Analysis of Security; Quantum Key; Distribution Based; Entangled Photon Pairs; Model Checking; in silico Development; Synthetic Gp 46-gp21; P400-P197 Peptide mimetic; pharmacophore; HTLV-1 Fusion Inhibitor; mass-action law; new cluster of algorithms;Cryptography, Quantum Cryptography, Quantum Key Distribution, Model Checking

Abstract

BACE-1 is the β-secretase responsible for the initial amyloidogenesis in Alzheimer’s disease, catalyzing hydrolytic cleavage of substrate in a pH-sensitive manner. The catalytic mechanism of BACE-1 requires water-mediated proton transfer from aspartyl dyad to the substrate, as well as structural flexibility in the flap region. Thus, the coupling of protonation and conformational equilibria is essential to a full in silico characterization of BACE-1. In this work, we perform constant pH replica exchange molecular dynamics simulations on both apo BACE-1 and five BACE-1-inhibitor complexes to examine the effect of pH on dynamics and inhibitor binding properties of BACE-1. Formation of insoluble amyloid plaques in the vascular and hippocampal areas of the brain characterizes Alzheimer’s disease, a devastating neurodegenerative disorder causing dementia. Site-specific hydrolytic catalysis of β-secretase, or BACE-1, is responsible for production of oligomerative amyloid β-peptide. As the catalytic activity of BACE-1 is pH-dependent and its structural dynamics are intrinsic to the catalysis, we examine the dependence of dynamics of BACE-1 on solution pH and its implications on the catalytic mechanism of BACE-1. Also, we highlight the importance of accurate description of protonation states of the titratable groups in computer-aided drug discovery targeting BACE-1. We hope the understanding of pH dependence of the dynamics and inhibitor binding properties of BACE-1 will aid the structure-based inhibitor design efforts against Alzheimer’s disease.Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria Discovery and a computerized quantitative bio-informatic in silico Development of a Synthetic Gp 46-gp21 derived P400-P197 Peptide mimetic pharmacophore as a potential HTLV-1 Fusion Inhibitor in a mass-action law based new cluster of algorithmsSensing of molecules using quantum dynamics. In our simulations, we find that solution pH controls the conformational flexibility of apo BACE-1, whereas bound inhibitors largely limit the motions of the holo enzyme at all levels of pH. The microscopic pKa values of titratable residues in BACE-1 including its aspartyl dyad are computed and compared between apo and inhibitor-bound states. Changes in protonation between the apo and holo forms suggest a thermodynamic linkage between binding of inhibitors and protons localized at the dyad. Utilizing our recently developed computational protocol applying the binding polynomial formalism to the constant pH molecular dynamics (CpHMD) framework, we are able to obtain the pH-dependent binding free energy profiles for various BACE-1-inhibitor complexes. Our results highlight the importance of correctly addressing the binding-induced protonation changes in protein-ligand systems where binding accompanies a net proton transfer. This work comprises the first application of our CpHMD-based free energy computational method to protein-ligand complexes and illustrates the value of CpHMD as an all-purpose tool for obtaining pH-dependent dynamics and binding free energies of biological systems.Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria Discovery and a computerized quantitative bio-informatic in silico Development of a Synthetic Gp 46-gp21 derived P400-P197 Peptide mimetic pharmacophore as a potential HTLV-1 Fusion Inhibitor in a mass-action law based new cluster of algorithmsSensing of molecules using quantum dynamics.

Keywords

Conformational Dynamics; Binding Free Energies; Inhibitors of BACE-1; Perspective of Protonation; Equilibria Discovery; computerized quantitative bio-informatic; in silico Development; Synthetic Gp 46-gp21; P400-P197 Peptide mimetic; pharmacophore; HTLV-1 Fusion Inhibitor; mass-action law; new cluster of algorithms;Sensing of molecules; quantum dynamics;

Abstract

Fluorescence molecular imaging/tomography may play an important future role in preclinical research and clinical diagnostics. Time- and frequency-domain fluorescence imaging can acquire more measurement information than the continuous wave (CW) counterpart, improving the image quality of fluorescence molecular tomography. Although diffusion approximation (DA) theory has been extensively applied in optical molecular imaging, high-order photon migration models need to be further investigated to match quantitation provided by nuclear imaging. In this paper, a frequency-domain parallel adaptive finite element solver is developed with simplified spherical harmonics (SPN) approximations. To fully evaluate the performance of the SPN approximations, a fast time-resolved tetrahedron-based Monte Carlo fluorescence simulator suitable for complex heterogeneous geometries is developed using a convolution strategy to realize the simulation of the fluorescence excitation and emission. The validation results show that high-order SPN can effectively correct the modeling errors of the diffusion equation, especially when the tissues have high absorption characteristics or when high modulation frequency measurements are used. Furthermore, the parallel adaptive mesh evolution strategy improves the modeling precision and the simulation speed significantly on a realistic digital mouse phantom. This solver is a promising platform for fluorescence molecular tomography using high-order approximations to the radiative transfer equation to Represent Entangled Quantum parallel adaptive finite element simplified spherical harmonics States approximation solver for frequency domain fluorescence molecular imaging to identify several global patterns for anti-HIV-1 cell cycle viral replication enzymes for the efficient discovery of homomultimerized HIV short linear motif-like peptide mimicking lead compound on its functional binding sites.

Keywords

A parallel adaptive finite element simplified spherical harmonics approximation solver for frequency domain fluorescence molecular imagingA cursory analysis to identify several global patterns for anti-HIV-1 cell cycle viral replication enzymes for the efficient discovery of homomultimerized HIV short linear motif-like peptide mimicking lead compound on its functional binding sites. Virtual Numbers to Represent Entangled Quantum States.

Abstract

To enhance the optimization ability of particle swarm algorithm, a novel quantum-inspired particle swarm optimization algorithm is proposed. In this method, the particles are encoded by the probability amplitudes of the basic states of the multi-qubits system. The rotation angles of multi-qubits are determined based on the local optimum particle and the global optimal particle, and the multi-qubits rotation gates are employed to update the particles. At each of iteration, updating any qubit can lead to updating all probability amplitudes of the corresponding particle. The experimental results of some benchmark functions optimization show that, although its single step iteration consumes long time, the optimization ability of the proposed method is significantly higher than other similar algorithms representing for the first time a Quantum-Inspired Particle Swarm Optimization Algorithm Encoded by Probability Amplitudes of Multi-Qubit cursory analysis to identify several global patterns for anti-HIV-1 cell cycle viral replication enzymes for the efficient discovery of homomultimerized HIV short linear motif-like peptide mimicking lead compound on its functional binding sites.

Keywords

cursory analysis; global patterns; anti-HIV-1; cell cycle viral replication enzymes; discovery of homomultimerized; HIV short linear motif-like; peptide mimicking; lead compound; functional binding sites; Quantum-Inspired; Particle Swarm; Optimization Algorithm; Probability Amplitudes of Multi-Qubits;