Abstract

Cancer is still a major cause of death in the world at the beginning of the- 21st century and remains a major focus for ongoing research and development. In recent years a promising approach to the therapeutic intervention of cancer has focused on antiangiogenesis therapies. This approach to intervening in cancer progression takes advantage of the idea that inhibiting or otherwise limiting the blood supply to tumors will deplete the tumor of oxygen and nutrients and will cause arrest of tumor cell growth and proliferation. This approach has been found to be effective and there are presently over 20 anti-angiogenic drugs undergoing various stages of evaluation in phase I, II or III clinical trials and numerous others in preclinical development. Vascular endothelial growth factor receptor 3 (VEGFR-3) supports tumor lymph angiogenesis. It was originally identified as a lymphangiogenic factor expressed in lymphatic endothelial cells. VEGFR-3 was detected in advanced human malignancies and correlated with poor prognosis. Previous studies show that activation of the VEGF-C/VEGFR-3 axis promotes cancer metastasis and is associated with clinical progression in patients with lung cancer, indicating that VEGFR-3 is a potential target for cancer therapy. By using a fast path planning approach, we then rapidly generated large amounts of flexible peptide conformations, allowing backbone and side chain flexibility. A newly introduced binding energy funnel ‘steepness score’ was applied for the evaluation of the protein–peptide-multi-ligand complexes binding affinity. KNIME-based BiogenetoligandorolTM – Pepcrawler simulations predicted high binding affinity for native protein–peptide-hyper-ligand complexes benchmark and low affinity for low-energy decoy complexes. As a result we managed finally to introduce an algorithm for high-resolution refinement and binding affinity estimation of novel designed inhibitors consisting of CGQMCTVWCSSGC conserved peptide substitution mimetic linked pharmaco-structures with potential antagonizing VEGFR-3-mediated oncogenic effects.

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 discovery process. In this science project we perfomed an in silico ChemoProteomic Prediction-Scan for the generation of Antigenic PatternLFA-3/IgG fusion polypeptide aa95-104FMGFNCGNCK; aa175-182 LFVWMHYY; aa176-190FVWMHYYVSMDALLG; aa222-236IQKLTGDENFTIPYW, and aa233-247IPYWDWRDAEKCDICmimetic pharmacophore on conserved Vitiligo post-trancripts domains.

Abstract

RPeptides derived from the C-terminal heptad repeat 2 (HR2) region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very efficient HIV-1 fusion inhibitors. It has previously been developed innovative gene therapeutic approaches aiming at the direct in vivo production of C peptides from genetically modified host cells and found that T cells expressing membrane-anchored or secreted C peptides are protected from HIV-1 infection. However, an unwanted immune response against such antiviral peptides may significantly impair clinical efficacy and pose safety risks to patients. To overcome this problem,a novel C peptide, V2o, was engineered with greatly reduced immunogenicity and excellent antiviral activity. V2o is based on the chimeric C peptide C46-EHO, which is derived from the HR2 regions of HIV-2EHO and HIV-1HxB2 and has broad anti-HIV and anti-simian immunodeficiency virus activity. The DINIES server accepts any ‘profiles’ or precalculated similarity matrices (or ‘kernels’) of drugs and target proteins in tab-delimited file format. When a training data set is submitted to learn a predictive model, users can select either known interaction information in the KEGG DRUG database or their own interaction data. Here, in Biogenea we have for the first time discovered an In silico designed Wilms’ Tumour 1 (WT1) peptide mimetic of high binding free energy with cancer vaccine like potential properties as a future pharmacophore loaded druggable molecule for the vaccination of patients with acute myeloid leukaemia by inducing a short-lived WT1-specific immune responses Immunogenicity and in siolico generated by the BAiogenetoligandorolTM and the DINIES. A drug–target interaction network inference engine based on supervised analysis.

Abstract

C-type natriuretic peptide (CNP), secreted by vascular endothelial cells, belongs to a family of peptides that includes atrial and brain natriuretic peptides. CNP exhibits many vasoprotective effects against pulmonary hypertension and pulmonary fibrosis.. In lungs of CNP-treated mice, expression of the monocyte chemoattractant protein-1, S100A8, and E-selectin genes was significantly lower than that in vehicle-treated mice. CNP had a protective effect on ALI induced by LPS by reducing inflammatory cell infiltration. CNP may hold promise in therapeutic strategies for ALI after pulmonary resection surgery. The continuous molecular fields (CMF) approach is based on the application of continuous functions for the description of molecular fields instead of finite sets of molecular descriptors (such as interaction energies computed at grid nodes) commonly used for this purpose. These functions can be encapsulated into kernels and combined with kernel-based machine learning algorithms to provide a variety of novel methods for building classification and regression structure-activity models, visualizing chemical datasets and conducting virtual screening. In this Research and Scientific Project, the CMF approach is applied to building 3D-QSAR models for 8 datasets through the use of five types of molecular fields (the electrostatic, steric, hydrophobic, hydrogen-bond acceptor and donor ones), the linear convolution molecular kernel with the contribution of each atom approximated with a single isotropic Gaussian function, and the kernel ridge regression data analysis technique. Here, in Biogenea Pharmaceuticals Ltd we discovered for the first time the GENEA-Natriolipontin-0073. An In silico designed of a C-type natriuretic mimetic peptide pharmacophore for the attenuation of lipopolysaccharide-induced acute lung injury using continuous molecular fields approaches to building 3D-QSAR models.

Abstract

The effectivenes of cancer vaccines in inducing CD8+Tcell responses remains a challenge, resulting in a need for testing more potent adjuvants. In previous clinical trials it has been determined the safetyand immunogenicity of vaccination against melanoma-related antigens employing MART-1,gp100, and tysosinase paptides combined with the TLR-9 agonist PF-3512676 and local GM-CSFin-oil emulsion.Using continuous monitoring of safety and a two-stage design for immunological efficacy, More than 20 immune-response evaluable patients were targetted. Vaccinations were given subcutaneously ondays 1 and 15 per cycle (1 cycle=28 days) for up to 13 cycles. Structure-based virtual screening of molecular compound libraries is a potentially powerful and inexpensive method for the discovery of novel lead compounds for drug development. That said, virtual screening is heavily dependent on detailed understanding of the tertiary or quaternary structure of the protein target of interest, including knowledge of the relevant binding pocket. Here, in Biogenea we have for the first time discovered a Safe and immunogenic pharmacophore activator mimic physicochemical properties of the MART-1 (26-35,27L), gp100 (209-217, 210M), and tyrosinase (368-376, 370D) inadjuvantwith PF-3512676 and GM-CSF as a future anti-cancer agent in metastatic melanoma conditions introducing a novel multi-parametric algorithm drug discovery approach using a Ligand-Based Virtual Screening approach through a Support Vector Machine and Information Fusion attempt.

Abstract

Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, such as ipilimumab, have generated measurable immune responses to Melan-A, NY-ESO-1, and gp100 antigens in metastatic melanoma. Vaccination against such targets has potential forimmunogenicity and may produce an effector memory T-cell response. It has been previously determined the effect of CTLA-4 blockador on antigen-specific responses following vaccination. In-depth immune monitoring was performed on three ipilimumab-treated patientsprevaccinated with gp100 DNA (IMF-24), gp100209–217 and tyrosinase peptides plus GM-CSFDNA (IMF-32), or NY-ESO-1 protein plus imiquimod (IMF-11). In previous studies it was shown that peripheral blood mononuclearcells were analyzed by tetramer and/or intracellular cytokine staining following 10-day culturewith HLA-A*0201-restricted gp100209–217 (ITDQVPFSV), tyrosinase369–377 (YMDGTMSQV),or 20-mer NY-ESO-1 overlapping peptides, respectively. It has also been evaluated on the PDBbind v2012 core set where istar platform combining with RF-Score manages to reproduce Pearson’s correlation coefficient and Spearman’s correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked conformation. Here, we have discovered for the first time an in silico predicted and computer-aided molecular designed CTLA-4 blockador for the increasement of the antigen-specific CD8+ T-cells to the inprevaccinated patients with melanoma using the istar. A Web Platform for Large-Scale Protein-Ligand Docking

Abstract

Variety of biological processes such as embryonic development, tissue remodeling and tissue repair involve controlled degradation of extra cellular matrix (ECM). This feature is a fundamental part of growth, invasion, and metastasis of malignant tumors. Matrix metalloproteinases (MMPs), a family of extracellular zinc-dependent neutral endopeptidases, are capable of degrading essentially all ECM components. They are the prime factors indulged in breaking down the extracellular matrix contributing to disease states such as arthritis, atherosclerosis, tumor cell invasion and metastasis. Collagenases show interesting differences in the crystal structures, despite being highly homologous to one another. Therefore, specific inhibition of MMP-1, MMP-8 and MMP-13 are considered to be an attractive target in drug discovery research. This in turn would be able to provide useful knowledge for developing specific new and active drug candidates targeting collagenases (MMP-1, MMP-8 and MMP-13). Computational design has the potential to provide a general, complementary approach for small molecule recognition in which design features and selectivity can be rationally programmed. The development of robust computational methods for the design of small molecule-binding proteins with high affinity and selectivity would have wide-ranging applications. The goal of existing methods for computational enzyme-derived conserved motif like peptide mimetic pharmaco-ligand design is to promote catalysis by creating energetically favorable hydrogen bonding, van der Waals, and electrostatic interactions to a high-energy reaction transition state(s) and/or intermediate(s). Although these interactions are also important for stabilizing the bound ground-state conformations of protein-small nano-linked druggable active conserved molecule complexes, they are not the sole determinant of small molecule binding. In this research study we have for the first time in silico discovered novel collagenase inhibitors using pharmacophore and structure based studies. We finally generated pharmacophore models using combined chemical informatic software for a diverse set of the fragmentation of the existing collagenase inhibitors (MMP-1, MMP-8 and MMP-13) with an aim to Lead identify and computer-aided molecular optimized of novel collagenase inhibitors consisting of a recored VAAHE/PRCGNPD peptidomimic highthroughput screened pharmacophore features to matrix contributing to disease arthritis states.

Abstract

In silico Drug discovery and development of novel multi-target molecules is an interdisciplinary, expensive and time-consuming procedure. Computer aided drug discovery advancements during the past decades have improved the way of pharmaceutical research design of novel bioactive huper-structured drug-gable molecules. Computer aided drug design helps in reducing the cost and time for drug discovery process which otherwise takes many years. Virtual screening and docking studies helped to obtain ligand molecules that can inhibit the important Proteins involved in the pathogenesis of Ebola virus. It is noticed that the chemical compounds might be the promising candidates drug-like small targeted compounds for further pre-clinical and clinical investigation, and that the NP and the octapeptides ATLQAIAS and ATLQAENV, as well as AVLQSGFR, might be pre-clinically translated and antisense converted to effective direct inhibitors against the Ebola Virus Fusion Conserved Proteoma. Meanwhile, we in silico generated conserved octapeptides mimotopic pharmaco-ligands based on the “distorted key energy binding fitness scoring” theory to in-silico anti-sense peptides by in-silico translate them and transform them into a scaffold energy hopping structure in order to design potent selective super-agonsist anti-peptide poly-mimic new superstructure which is explicitly elucidated. We also combined all existing methods for computational huper-structured drug design methodologies to induce catalysis of Ebola Virus EBOV NP and EBO16 peptides by inducing energetically targeted favorable hydrogen bonds, van der Waals, and electrostatic interactions to a high-energy reaction conserved motif-based transition state(s) and/or intermediate(s) of Ebola virus. In this present Research Scientific Project , for first time we developed a computational method for designing motif-like conserved residues and ligand binding virus proteins with two properties characteristic of naturally occurring binding sites in addition to specific energetically favorable interactions with our newly designed hyper-multi-target ligand. Here, in Biogenea we have in silico discovered a virion-attached pharmacophore cross-reacting synthetic EQHHRRTDN peptide mimetic ligand comprising potential therapeutic properties against Ebola virus using an in silico drug design structure peptide-sequence-based combinatorial analysis by a multi-objective cluster of algorithms.

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 strategy utilizing a mechanistic investigation of low mass stochastic genetic algorithms for the generation of an enantiomeric antitumor agent consistinc of three conserved pharmacophores dual targeting the p53 and NF-κB pathways for the activation of the p53 tumor suppressor pathway by an engineered TAT-SMAR1 wild type, P44 cyclotidomimic multicovalent pharmaco-ligand.

Abstract

4F is an anti-inflammatory, apolipoprotein A-I (apoA-I)-mimetic peptide that is active in vivo at nanomolar concentrations in the presence of a large molar excess of apoA-I. Physiologic concentrations (∼35 μM) of human apoA-I did not inhibit the production of LDL-induced monocyte chemotactic activity by human aortic endothelial cell cultures, but adding nanomolar concentrations of 4F in the presence of ∼35 μM apoA-I significantly reduced this inflammatory response. A common strategy for virtual screening considers a systematic docking of a large library of organic compounds into the target sites in protein receptors with promising leads selected based on favorable intermolecular interactions. Despite a continuous progress in the modeling of protein-ligand interactions for pharmaceutical design, important challenges still remain, thus the development of novel techniques is required. Pearson correlation coefficient between experimental and predicted by eSimDock Ki values for a large data set of the crystal structures of protein-ligand complexes from BindingDB is 0.58, which decreases only to 0.46 when target structures distorted to 3.0 Å Cα-RMSD are used. These encouraging results show that the performance of eSimDock is largely unaffected by the deformations of ligand binding regions, thus it represents a practical strategy for across-proteome virtual screening using protein models.Here, in Biogenea Pharmaceuticals Ltd we discovered for the first time the GENEA-Apo-I009. A Rational designed ApoA-I Mimetic-polypharmacophorIC hyper ligand as an in silico improved innovative and potential anti-inflammatory agent, computer-aided generated by integrating nonlinear scoring functions for a similarity-based ligand docking and binding affinity prediction approach.