Extracting prime protein targets as possible drug candidates: machine learning evaluation.

Extracting "high ranking" or "prime protein targets" (PPTs) as potent MRSA drug candidates from a given set of ligands is a key challenge in efficient molecular docking. This study combines protein-versus-ligand matching molecular docking (MD) data extracted from 10 independent molecular docking (MD) evaluations - ADFR, DOCK, Gemdock, Ledock, Plants, Psovina, Quickvina2, smina, vina, and vinaxb to identify top MRSA drug candidates. Twenty-nine active protein targets (APT) from the enhanced DUD-E repository ( http://DUD-E.

Towards Effective Consensus Scoring in Structure-Based Virtual Screening.

Virtual screening (VS) is a computational strategy that uses in silico automated protein docking inter alia to rank potential ligands, or by extension rank protein-ligand pairs, identifying potential drug candidates. Most docking methods use preferred sets of physicochemical descriptors (PCDs) to model the interactions between host and guest molecules. Thus, conventional VS is often data-specific, method-dependent and with demonstrably differing utility in identifying candidate drugs.

To Affinity and Beyond: A Personal Reflection on the Design and Discovery of Drugs.

Faced with new and as yet unmet medical need, the stark underperformance of the pharmaceutical discovery process is well described if not perfectly understood. Driven primarily by profit rather than societal need, the search for new pharmaceutical products-small molecule drugs, biologicals, and vaccines-is neither properly funded nor sufficiently systematic. Many innovative approaches remain significantly underused and severely underappreciated, while dominant methodologies are replete with problems and limitations.

West Nile Virus Vaccine Design by T Cell Epitope Selection: Analysis of Conservation, Functional Cross-Reactivity with the Human Genome, and Population Coverage.

West Nile Virus (WNV) causes a debilitating and life-threatening neurological disease in humans. Since its emergence in Africa 50 years ago, new strains of WNV and an expanding geographical distribution have increased public health concerns. There are no licensed therapeutics against WNV, limiting effective infection control.

Correction to: Computational assembly of a human Cytomegalovirus vaccine upon experimental epitope legacy.

After publication of the original article [1], we were notified that legends of Fig. 1 and Fig. 2 have been swapped.

Drug Discovery: Today and Tomorrow.

Drug discovery continues to underperform relative to unmet medical need. Driven by profit not societal need, the search for new drugs is neither properly funded nor sufficiently systematic. Many innovative approaches are significantly underused yet extant methodology is replete with problems.

Computational assembly of a human Cytomegalovirus vaccine upon experimental epitope legacy.

Background: Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus affecting approximately 90% of the world population. HCMV causes disease in immunologically naive and immunosuppressed patients. The prevention, diagnosis and therapy of HCMV infection are thus crucial to public health.

VaxiJen Dataset of Bacterial Immunogens: An Update.

Background: Identifying immunogenic proteins is the first stage in vaccine design and development. VaxiJen is the most widely used and highly cited server for immunogenicity prediction. As the developers of VaxiJen, we are obliged to update and improve it regularly.

Selection-based design of in silico dengue epitope ensemble vaccines.

Dengue virus affects approximately 130 countries. Twenty-five percentage of infections result in febrile, self-limiting illness; heterotypic infection results in potentially fatal dengue haemorrhagic fever or dengue shock syndrome. Only one vaccine is currently available.

In silico design of Mycobacterium tuberculosis epitope ensemble vaccines.

Effective control of Mycobacterium tuberculosis is a global necessity. In 2015, tuberculosis (TB) caused more deaths than HIV. Considering the increasing prevalence of multi-drug resistant forms of M.

In silico prediction of cancer immunogens: current state of the art.

Cancer kills 8 million annually worldwide. Although survival rates in prevalent cancers continue to increase, many cancers have no effective treatment, prompting the search for new and improved protocols. Immunotherapy is a new and exciting addition to the anti-cancer arsenal.

In silico design of knowledge-based Plasmodium falciparum epitope ensemble vaccines.

Malaria is a global health burden, and a major cause of mortality and morbidity in Africa. Here we designed a putative malaria epitope ensemble vaccine by selecting an optimal set of pathogen epitopes. From the IEDB database, 584 experimentally-verified CD8+ epitopes and 483 experimentally-verified CD4+ epitopes were collected; 89% of which were found in 8 proteins.

Designing Epitope Ensemble Vaccines against TB by Selection: Prioritizing Antigens using Predicted Immunogenicity.

Tuberculosis (TB) is a global health burden, and a major cause of mortality and morbidity in West Africa. Here, we select key conserved pathogen epitopes of proven immunogenicity to form a potential TB epitope ensemble vaccine. We compared two vaccine formulations: one comprising class I epitopes from the 13 most prevalent class I epitope-bearing antigens and class II epitopes deriving from the 20 most prevalent class II epitope-bearing antigens and another consisting of epitopes derived solely from 5 antigens identified as the most immunogenic by VaxiJen.

Scrutinizing human MHC polymorphism: Supertype analysis using Poisson-Boltzmann electrostatics and clustering.

Peptide-binding MHC proteins are thought the most variable across the human population; the extreme MHC polymorphism observed is functionally important and results from constrained divergent evolution. MHCs have vital functions in immunology and homeostasis: cell surface MHC class I molecules report cell status to CD8+ T cells, NKT cells and NK cells, thus playing key roles in pathogen defence, as well as mediating smell recognition, mate choice, Adverse Drug Reactions, and transplantation rejection. MHC peptide specificity falls into several supertypes exhibiting commonality of binding.

Protein lipograms.

Linguistic analysis of protein sequences is an underexploited technique. Here, we capitalize on the concept of the lipogram to characterize sequences at the proteome levels. A lipogram is a literary composition which omits one or more letters.

Towards the knowledge-based design of universal influenza epitope ensemble vaccines.

Motivation: Influenza A viral heterogeneity remains a significant threat due to unpredictable antigenic drift in seasonal influenza and antigenic shifts caused by the emergence of novel subtypes. Annual review of multivalent influenza vaccines targets strains of influenza A and B likely to be predominant in future influenza seasons. This does not induce broad, cross protective immunity against emergent subtypes.

In Silico Adjuvant Design and Validation.

Adjuvants are substances that boost the protective immune response to vaccine antigens. The majority of known adjuvants have been identified through the use of empirical approaches. Our aim was to identify novel adjuvants with well-defined cellular and molecular mechanisms by combining a knowledge of immunoregulatory mechanisms with an in silico approach.

A Cohesive and Integrated Platform for Immunogenicity Prediction.

In silico methods for immunogenicity prediction mine the enormous quantity of data arising from deciphered genomes and proteomes to identify immunogenic proteins. While high and productive immunogenicity is essential for vaccines, therapeutic proteins and monoclonal antibodies should be minimally immunogenic. Here, we present a cohesive platform for immunogenicity and MHC class I and/or II binding affinity prediction.

EPIPOX: Immunoinformatic Characterization of the Shared T-Cell Epitome between Variola Virus and Related Pathogenic Orthopoxviruses.

Concerns that variola viruses might be used as bioweapons have renewed the interest in developing new and safer smallpox vaccines. Variola virus genomes are now widely available, allowing computational characterization of the entire T-cell epitome and the use of such information to develop safe and yet effective vaccines. To this end, we identified 124 proteins shared between various species of pathogenic orthopoxviruses including variola minor and major, monkeypox, cowpox, and vaccinia viruses, and we targeted them for T-cell epitope prediction.

Accurate estimation of isoelectric point of protein and peptide based on amino acid sequences.

Motivation: In any macromolecular polyprotic system-for example protein, DNA or RNA-the isoelectric point-commonly referred to as the pI-can be defined as the point of singularity in a titration curve, corresponding to the solution pH value at which the net overall surface charge-and thus the electrophoretic mobility-of the ampholyte sums to zero. Different modern analytical biochemistry and proteomics methods depend on the isoelectric point as a principal feature for protein and peptide characterization. Protein separation by isoelectric point is a critical part of 2-D gel electrophoresis, a key precursor of proteomics, where discrete spots can be digested in-gel, and proteins subsequently identified by analytical mass spectrometry.

A statistical physics perspective on alignment-independent protein sequence comparison.

Motivation: Within bioinformatics, the textual alignment of amino acid sequences has long dominated the determination of similarity between proteins, with all that implies for shared structure, function and evolutionary descent. Despite the relative success of modern-day sequence alignment algorithms, so-called alignment-free approaches offer a complementary means of determining and expressing similarity, with potential benefits in certain key applications, such as regression analysis of protein structure-function studies, where alignment-base similarity has performed poorly.

Results: Here, we offer a fresh, statistical physics-based perspective focusing on the question of alignment-free comparison, in the process adapting results from 'first passage probability distribution' to summarize statistics of ensemble averaged amino acid propensity values.

PIP-DB: the Protein Isoelectric Point database.

Unlabelled: A protein's isoelectric point or pI corresponds to the solution pH at which its net surface charge is zero. Since the early days of solution biochemistry, the pI has been recorded and reported, and thus literature reports of pI abound. The Protein Isoelectric Point database (PIP-DB) has collected and collated these data to provide an increasingly comprehensive database for comparison and benchmarking purposes.

Computational modelling approaches to vaccinology.

Excepting the Peripheral and Central Nervous Systems, the Immune System is the most complex of somatic systems in higher animals. This complexity manifests itself at many levels from the molecular to that of the whole organism. Much insight into this confounding complexity can be gained through computational simulation.