Abstract

Near linear scaling fragment based quantum chemical calculations are becoming increasingly popular for treating large systems with high accuracy and is an active field of research. However, it remains difficult to set up these calculations without expert knowledge. To facilitate the use of such methods, software tools need to be available to support these methods and help to set up reasonable input files which will lower the barrier of entry for usage by non-experts. Previous tools relies on specific annotations in structure files for automatic and successful fragmentation such as residues in PDB files. We present a general fragmentation methodology and accompanying tools called FragIt to help setup these calculations. FragIt uses the SMARTS language to locate chemically appropriate fragments in large structures and is applicable to fragmentation of any molecular system given suitable SMARTS patterns. We present SMARTS patterns of fragmentation for proteins, DNA and polysaccharides, specifically for D-galactopyranose for use in cyclodextrins. FragIt is used to prepare input files for the Fragment Molecular Orbital method in the GAMESS program package, but can be extended to other computational methods easily.FragIt: A Tool to Prepare Input Files for Fragment Based Quantum Chemical CalculationsA rational in silico drug-target flexibility complement methodology-design for the generation of a peptide-mimic novel pharmacoelement binding to the amino acid conserved sequences of the active loop of a Haemophilus influenzae porin P2.FragIt: A Tool to Prepare Input Files for Fragment Based Quantum Chemical Calculations. Haemophilus influenzae type b (Hib) is one of the leading causes of invasive bacterial infection in young children. It is characterized by inflammation that is mainly mediated by cytokines and chemokines. One of the most abundant components of the Hib outer membrane is the P2 porin, which has been shown to induce the release of several inflammatory cytokines. A synthetic peptide corresponding to loop L7 of the porin activates JNK and p38 mitogen-activated protein kinase (MAPK) pathways. It has also been reported that a novel use of the complementary peptide approach to design a peptide that is able to bind selectively to the protein P2, thereby reducing its activity. In this in silico study we used of higher levels of our complement conserved structure ligand based binding pocket drug interactive theory to increase the accuracy of protein-ligand binding affinity predictions, resulting in better hit identification success rates as well as more efficient lead optimization processes. Here, we discovered for the first time the GENEA-Poriflunzaten-5567 a Peptide-mimic novel pharmacoelements complementary to the active loop of porin P2 from Haemophilus influenzae for the annotated modulation of its activity using a rational in silico drug-target flexibility complement methodology-design to Prepare Input Files for Fragment Based Quantum Chemical Calculations for the generation of a peptide-mimic novel pharmacoelement binding to the amino acid conserved sequences of the active loop Haemophilus influenzae porin P2.

Keywords

combined-application;knowledge-based;scoring;physical;-forcefield;-based hit-scoring;functions; rational; in silico drug-target; flexibility; complement; methodology-design; peptide-mimic; novel pharmacoelement; amino acid; conserved sequences; active loop; Haemophilus influenzae; porin P2;. Input Files; Fragment Based; Quantum Chemical Calculations;

Abstract

The need to compute molecular properties for larger and larger systems with desirable accuracy has led to the development of novel methods such as fragmentation methods [1]. In fragmentation methods, a large system is divided into several smaller subsystems called fragments. Each fragment is treated with some ab initio level of theory and different methods [2]–[7] include the surrounding environment in different ways. In this work, we are interested in setting up Fragment Molecular Orbital (FMO) [5], [6] and Effective Fragment Molecular Orbital (EFMO) [8], [9] calculations, but our method is extensible to other fragment based methods. In the FMO method, each fragment is polarized by the presence of the Coulomb field of all other fragments. The underlying equations allow for a systematic improvement of the energy by considering pairs and optionally triples of fragments [10], the latter often within milihartree accuracy of the corresponding ab initio energy. FMO supports correlated treatment of one or more fragments [11]–[13] as well the possibility of obtain excitation energies with good accuracy. [14] The FMO method in GAMESS [15] utilizes a novel parallelization scheme [16] to allow computations to be carried out efficiently on desktop computers as well as large scale super computers. [17] Fragmentation can occur across covalent bonds using either the Hybrid Orbital Projection (HOP) [18] or Adapted Frozen Orbital (AFO) [19], [20] method. The EFMO method, also available in GAMESS, neglects the Coulomb bath from FMO and replaces it with classical terms to improve the computational speed to Prepare Input Files for Fragment Based Quantum Chemical Calculations for in silico drug-target flexibility complement methodology-design for the generation of a peptide-mimic novel pharmacoelement binding to the active loop of a Haemophilus influenzae porin P2 amino acid conserved sequences.

Keywords

rational Tool; Input Files; Fragment Based; Quantum Chemical Calculations; drug-target flexibility; complement methodology-design; peptide-mimic; novel pharmacoelement; active loop; Haemophilus influenzae; porin P2; amino acid; conserved sequences.

Abstract

Near linear scaling fragment based quantum chemical calculations are becoming increasingly popular for treating large systems with high accuracy and is an active field of research. However, it remains difficult to set up these calculations without expert knowledge. To facilitate the use of such methods, software tools need to be available to support these methods and help to set up reasonable input files which will lower the barrier of entry for usage by non-experts. Previous tools relies on specific annotations in structure files for automatic and successful fragmentation such as residues in PDB files. We present a general fragmentation methodology A Tool to Rationally in silico Identification of a immunogenic MAGED4B peptide-mimetic Prepare Input Files for Fragment Based Quantum Chemical Calculations on pharmacophoric robust agent as a potential fragment-library derived drug-compound comprising vaccine mimic annotated properties in oral cancer immunotherapies and accompanying tools to help setup these calculations.

Keywords

genetic-algorithm;(meta)-ensembles-approach;binary-classification;ligand-based;drug, design; MAGED4; Boral cancer immunotherapies, Input Files; Fragment Based Quantum; Chemical Calculations; Rationally; in silico Identification; immunogenic; MAGED4B peptide-mimetic; pharmacophoric; robust agent; fragment-library; drug-compound; vaccine mimic annotated properties; oral cancer immunotherapies.

Abstract

Background

Molecular docking simulation is the Rational Drug Design (RDD) step that investigates the affinity between protein receptors and ligands. Typically, molecular docking algorithms consider receptors as rigid bodies. Receptors are, however, intrinsically flexible in the cellular environment. The use of a time series of receptor conformations is an approach to explore its flexibility in molecular docking computer simulations, but it is extensively time-consuming. Hence, selection of the most promising conformations can accelerate docking experiments and, consequently, the RDD efforts. It has been previosuly reported that lipopeptides can be used to elicit cytotoxic T lymphocyte (CTL) responses against viral diseases and cancer. In previous scientific projects, it has also been determined that mono-palmitoylated peptides can enhance anti-tumor responses in the absence of adjuvant activity. To investigate whether di-palmitoylated peptides with TLR2 agonist activity are able to induce anti-tumor immunity, it was previously synthesized a di-palmitic acid-conjugated long peptide that contains a murine CTL epitope of HPV E749-57 (Pam2IDG). Pam2IDG stimulated the maturation of bone marrow-derived dendritic cells (BMDCs) through TLR2/6. After immunization, Pam2IDG induced higher levels of T cell responses than those obtained with its non-lipidated counterpart (IDG). Here, we present a novel approach based on GRID molecular interaction fields and the derivative peptide mimicking rationally drug discovery method that has been previously utilized, which may provides a common reference to compare both small molecule ligands and conserved fragment-peptide targeting. Unlike classical pharmacophore elucidation approaches that extract simplistic molecular features, determine those which are common across the data set, and use these features to align the structures and subsequently extracts the common interacting features in terms of their molecular interaction fields, pseudofields, and atomic points, representing the common pharmacophore as a more comprehensive pharmacophoric pseudomolecule. Our fragment-ligand based drug discovery approach is applied to a number of data sets to investigate performance in terms of reproducing the X-ray crystallography-based alignment, in terms of its discriminatory ability when applied to virtual screening and also to illustrate its ability to explain alternative binding modes. As a result we discovered for the first time the GENEA-Tollarepomir-5579, a Toll-like receptor agonist-conjugated peptide-mimetic pharmacophoric multi-targeted agent utilizing a comprehensive source and free tool for assessment of an in silico annotated drug discovery interactive approach for Mining flexible-receptor docking experiments to select promising protein receptor snapshots on the depletion of tumor-associated macrophages by a computer-aided designed canditate druggable Toll-like receptor (Pam2IDG) peptide-domain targeted by a pharmacophoric mimetic agonistic agent.

Keywords

Toll-likereceptor;agonist-conjugated;peptide-mimetic;pharmacophoric;multi-targeted, Mining flexible-receptor docking experiments; select promising protein receptor; snapshots; in silico; annotated drug discovery interactive approach; depletion tumor-associated macrophages; computer-aided; canditate druggable; Toll-like receptor; (Pam2IDG) peptide-domain; targeted; pharmacophoric; mimetic agonistic agent.

Abstract

Steering quantum dynamics such that the target states solve classically hard problems is paramount to quantum simulation and computation. And beyond, quantum control is also essential to pave the way to quantum technologies. Here, important control techniques are reviewed and presented in a unified frame covering quantum computational gate synthesis and spectroscopic state transfer alike. We emphasize that it does not matter whether the quantum states of interest are pure or not. While pure states underly the design of quantum circuits, ensemble mixtures of quantum states can be exploited in a more recent class of algorithms: it is illustrated by characterizing the Jones polynomial in order to distinguish between different (classes of) knots. Further applications include Josephson elements, cavity grids, ion traps and nitrogen vacancy centres in scenarios of closed as well as open quantum systems.Control aspects of quantum computing using pure and mixed states Control aspects of quantum computing using pure and mixed states A Computer-aided rational approach for the in silico generation of a TCR Peptide Mimetic Pharmacoligand as a potential chemo-modulator in Human Autoimmune Diseases.Inflammatory Th1 cells reacting to tissue/myelin derived antigens likely contribute to the pathogenesis of diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis. One regulatory mechanism that may be useful for treating autoimmune diseases involves an innate second set of Th2 cells specific for portions of the T cell receptor of clonally expanded pathogenic Th1 cells. These Th2 cells are programmed to respond to internally modified V region peptides from the T cell receptor (TCR) that are expressed on the Th1 cell surface in association with major histocompatibility molecules. TB Mobile can now manage a small collection of compounds that can be imported from external sources, or exported by various means such as email or app-to-app inter-process communication. This means that TB Mobile can be used as a node within a growing ecosystem of mobile apps for cheminformatics. It can also cluster compounds and use internal algorithms to help identify potential targets based on quantum computing pure and mixed states of a Computer-aided rational approach for the in silico generation of a TCR Peptide Mimetic Pharmacoligand as a potential chemo-modulator in Human Autoimmune Diseases.

Keywords

Control aspects of quantum computing; pure and mixed states; Computer-aided rational approach; in silico; TCR Peptide; Mimetic Pharmacoligand; chemo-modulator; Human Autoimmune Diseases, optimal quantum control, quantum computing, unitary gate design, knot theory, Jones polynomial.

Abstract

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. 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.GEMS performs bicluster mining based on a Gibbs sampling paradigm of multi-mimotopic algorithmic approach for biclustering analysis of In silico designed expression data on an Anticancer Peptide SVS-1 multipharmacophore as a potential drug-like efficator in Preceding Membrane Neutralization.

Keywords

In silico designed; Anticancer Peptide SVS-1; multipharmacophore; drug-like; efficator in Preceding Membrane Neutralization; multi-mimotopic algorithmic approach; biclustering analysis; expression data.

Abstract

Vitiligo is a skin disorder characterized by selective melanocyte destruction and concomitant appearance of depigmented macules that over time enlarge, coalesce, and form patches. It has been suggested that vitiligo is, at least in part, caused by autoimmune responses mediated by cytotoxic T cells against melanocytes, causing depigmentation Immune responses contribute to the pathogenesis of vitiligo and target melanoma sometimes associated with vitiligo-like depigmentation in some melanoma patients. It has been perviously reported that the tyrosinase autoantigen was immunorecognized with the same molecular pattern by sera from vitiligo and melanoma patients. Five autoantigen peptides was found to compose the immunodominant antityrosinase response: aa95-104FMGFNCGNCK; aa175-182 LFVWMHYY; aa176-190FVWMHYYVSMDALLG; aa222-236IQKLTGDENFTIPYW, and aa233-247IPYWDWRDAEKCDIC. Synergistic therapies for the treatment of vitiligo are provided. The major therapies for the treatment of vitiligo a pigmentary disorder characterized by patchy depigmentation of skin are Psoralens plus UV-A, steroids, basic fibroblast growth factor (bFGF) peptide location or surgical procedures. Psoralens plus UV-A is effective in about 50% of cases, steroids are limitedly effective only in fast spreading cases of vitiligo and often reoccurs on stoppage of treatment. Surgical treatment is the last resort for vitiligo therapy, when all other therapies failed. It is limitedly effective. Basic fibroblast growth factor peptide(s) location was developed as a new mode therapy for the treatment of vitiligo. Therefore, SEQ ID NO: 01 VPHIPPN, SEQ ID NO: 02 MPPTQVS, SEQ ID NO: 03 QMHPWPP, SEQ ID NO: 1 1 LPLTPLP, SEQ ID NO: 12 QLNVNHQARADQ, SEQ ID NO: 13 TSASTRPELHYP, SEQ ID NO: 14 TFLPHQMHPWPP peptides, modified peptides and antibody or antibody fragments inhibiting the activity of MIA and can be used for treating vitiligo by inducing re-pigmentation. Fragment-based lead discovery is a method used for finding lead compounds as part of the drug in silico chemoproteomic prediction-scannings discovery process for the Quantum Dynamics in Continuum for Proton Transport I Basic Formulation of a tyrosinase aa95-104FMGFNCGNCK antigenic patternLFA-3/IgG fusion polypeptide IleAlaArgArgPheLeuOH (Kinetensin) mimetic pharmacophore on conserved Vitiligo post-trancripts domains.

Keywords

Quantum Dynamics; Continuum for Proton Transport I: Basic Formulation; in silico; chemoproteomic prediction-scannings; tyrosinase aa95-104FMGFNCGNCK; antigenic pattern;LFA-3/IgG fusion polypeptide; IleAlaArgArgPheLeuOH (Kinetensin); mimetic pharmacophore ;conserved Vitiligo; post-trancripts domains.

Abstract

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. 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.GEMS performs bicluster mining based on a Gibbs sampling Collapsing paradigm of a Perfect Superposition to an in silico Anticancer Peptide SVS-1 multipharmacophore Chosen Quantum State without expression data Measurements of the potential multi-mimotopic algorithmic biclustering analysis of drug-like efficators in Preceding Membrane Neutralization.

Keywords

Collapsing; Perfect Superposition; Chosen Quantum State; Measurement; In silico designed; Anticancer Peptide; SVS-1; multipharmacophore; drug-like; efficator; Preceding Membrane Neutralization; multi-mimotopic; algorithmic approach; biclustering analysis; expression data.

Abstract

Generation of non-classical states of light compatible with atomic quantum memory has been an outstanding challenge driven by various applications in quantum information processing [1]. Various approaches to generation of single photon states compatible with atoms have been pursued [2]: single atoms in free space [3] and in high-finesse cavities [4] and atomic ensembles [5], and non-classical features such as photon antibunching and violation of classical inequalities have been demonstrated. The ever-increasing number of tumor-associated antigens has provided a major stimulus for the development of therapeutic peptides vaccines. Tumor-associated peptides can induce high immune response rates and have been developed as vaccines for several types of solid tumors, and many are at various stages of clinical testing. MAGED4B, a melanoma antigen, is overexpressed in oral squamous cell carcinoma (OSCC) and this expression promotes proliferation and cell migration. In previous scientifc projects it has also been identified that 9 short peptides derived from MAGED4B protein are restricted in binding to the HLA subtypes common in the Asian population (HLA-A2, A11, and A24). As a result, we here discovered for the first time the GENEA-Immunomagetor-45700d utilizing the KNIME-BiogenetoligandorolTM-PASS-KNIME-based GA(M)E-QSAR-FIPSDock: a new molecular docking combinatorial clustering technique driven by fully informed swarm optimization algorithm and GA(M)E-QSAR: a novel, fully automatic genetic-algorithm-(meta)-ensembles approach for binary classification in ligand-based drug design based on Chemical and biological properties of frequent screening hits in predicting drug targets based on conserved binding pocket active MAGED4B protein domains of a Collapsing Perfect Superposition to a Chosen Quantum State without Measurements to a Rationally immunogenic MAGED4B peptide-mimetic pharmacophoric robust agent as a potential fragment-library derived drug-compound comprising vaccine mimic annotated properties in oral cancer immunotherapies.

Keywords

Collapsing a Perfect Superposition; Chosen Quantum State; Measurement; Rationally; in silico Identification; immunogenic MAGED4Bl peptide-mimeticl pharmacophoricl robust agentl fragment-library; drug-compound; vaccine mimic; annotated properties; oral cancer immunotherapies.

Abstract

The p53 and nuclear factor κB (NF-κB) pathways play crucial roles in human cancer development. Simultaneous targeting of both pathways is an attractive therapeutic strategy against cancer. The use of pharmacologically active short peptide sequences has prooven to be a better option in cancer therapeutics than the full-lengthprotein. It has been previously report ed one such 44-mer peptide sequence of SMAR1 (TAT-SMAR1 wild type, P44) that retains the tumor suppressor activity of the full-length protein.P44 peptide could efficiently activate p53 by mediating its phosphorylation at serine15, resulting in the activation of p21 and in effect regulating cell cycle checkpoint. In vitrophosphorylation assays with point-mutated P44-derived pep-tides suggested that serine 347 of SMAR1 was indispensable forits activity and represented the substrate motif for the proteinkinase C family of proteins. In this Research Scientific Project we generated an antitumor multi-targeted hyper-molecule that bears a pyrrolo[3,4-clomifene-diamizido-c]pyrazole scaffold and functions as an enantiomeric P44 peptide mimeto inhibitor against both the p53-MDM2 interaction and the NF-κB activation. This pharmacophjoric scaffold may be a first-in-class dual targeted enantiomeric inhibitor with dual efficacy for cancer therapy with potential synergistic effect in vitro and in vivo. Docking and molecular dynamics simulation studies further provided insights into the nature of stereoselectivity. Here, we have for the first time in silico discovered novel chemo-hyperstructures as a novel drug discovery incorporated novel Quantum Clock Synchronizations with a Single Qudit chemo-hyperstructure as a novel drug discovery dual targeting of the p53 and NF-κB pathways for the activation of the p53 tumor suppressor pathway by an engineered P44 cyclotidomimic agonisitic mechanistic pharmacoligand.

Keywords

Quantum Clock Synchronization; Single Qudit;In silico discovery; novel chemo-hyperstructure; novel drug discovery; dual targeting; p53;NF-κB pathways; tumor suppressor pathway; engineered P44; cyclotidomimic agonisitic; mechanistic pharmacoligand.