Chemoinformatics approaches for new drugs discovery

Chemoinformatics uses computational methods and technologies to solve chemical problems. It works on molecular structures, their representations, properties and related data. The first and most important phase in this field is the translation of interconnected atomic systems into in-silico models, ensuring complete and correct chemical information transfer. In the last 20 years the chemical databases evolved from the state of molecular repositories to research tools for new drugs identification, while the modern high-throughput technologies allow for continuous chemical libraries size increase as highlighted by publicly available repository like PubChem [http://pubchem.ncbi.nlm.nih.gov/], ZINC [http://zinc.docking.org/], ChemSpider[http://www.chemspider. com/]. Chemical libraries fundamental requirements are molecular uniqueness, absence of ambiguity, chemical correctness (related to atoms, bonds, chemical orthography), standardized storage and registration formats. The aim of this work is the development of chemoinformatics tools and data for drug discovery process. The first part of the research project was focused on accessible commercial chemical space analysis; looking for molecular redundancy and in-silico models correctness in order to identify a unique and univocal molecular descriptor for chemical libraries indexing. This allows for the 0%-redundancy achievement on a 42 millions compounds library. The protocol was implemented as MMsDusty, a web based tool for molecular databases cleaning. The major protocol developed is MMsINC, a chemoinformatics platform based on a starting number of 4 millions non-redundant high-quality annotated and biomedically relevant chemical structures; the library is now being expanded up to 460 millions compounds. MMsINC is able to perform various types of queries, like substructure or similarity search and descriptors filtering. MMsINC is interfaced with PDB(Protein Data Bank)[http://www.rcsb.org/pdb/home/home.do] and related to approved drugs. The second developed protocol is called pepMMsMIMIC, a peptidomimetic screening tool based on multiconformational chemical libraries; the screening process uses pharmacophoric fingerprints similarity to identify small molecules able to geometrically and chemically mimic endogenous peptides or proteins. The last part of this project lead to the implementation of an optimized and exhaustive conformational space analysis protocol for small molecules libraries; this is crucial for high quality 3D molecular models prediction as requested in chemoinformatics applications. The torsional exploration was optimized in the range of most frequent dihedral angles seen in X-ray solved small molecules structures of CSD(Cambridge Structural Database); by appling this on a 89 millions structures library was generated a library of 2.6 x 10 exp 7 high quality conformers. Tools, protocols and platforms developed in this work allow for chemoinformatics analysis and screening on large size chemical libraries achieving high quality, correct and unique chemical data and in-silico model

Molecular - bioassay methods: complementary approaches for development and evaluation of anti infective marine product

The current trends in drug development employ biotechnological approach to expedite effective drugs discovery program. Molecular biotechnological approach, in combination with bioassay, is practical in attaining effective drugs since the two platform methods complement each other by target identification, as well as compound screening, profiling and validation. The research on antimicrobial properties of marine products, targeting membrane function through membrane permeabilizing ability, has been carried out using molecular- and cellular-based approaches. The molecular approach for the screening of membrane permeabilizing peptide gene in local marine organism was found to successfully amplify a conserved gene sequence of the antibacterial peptide gene. Bacterial membrane permeabilizing ability of the methanolic extract was indicated through alteration of mRNA nucleotides, genes coding for membrane development in Staphylococcus aureus (MRSA) and the non-methicillin resistant strains. The alteration of nucleotides affected the transportation of lysine to the phospholipid bilayer of bacterial membranes, resulting in incomplete membrane structure, eventual lysis and cell death. Through cellular approaches, the methanolic extract of marine organisms affecting membranes of S. aureus, were confirmed. In specific, the extract showed a good inhibitory activity against S. aureus through plate and tube methods, and the cellular assay illustrated the penetration of fluorescence dye in treated bacterial pathogens, similar to the pathogens treated with positive antibiotic controls. The research constitutes a scientific advancement in the field of medical treatment of drug resistant bacteria and a forefront study of drugs discovery program focusing on drugs target genes

Identification and Characterization of Bioactive Components in Datura stramonium Leaves: an insight into Drugs Discovery

Medicines from plants help in treating ailments, but to utilize them effectively in the management of diseases requires the identification of potent phytochemicals relative to conventional drugs. These phytochemicals are compared with synthetics drugs in line with their treatment regimen. An investigation was designed to identify, and characterized the different phytochemicals in Datura stramonium (Jimson weed) leaves and compared them with conventional or standard drugs. The identified phytochemicals were blasted on the drugs bank website to find their correlation and relativity. GC/MS technique was used to analyze the phytochemicals. The results showed 80 different phytochemicals belonging to several categories of phytochemicals - alkaloids, flavonoids, terpenoids, saponins, amine, and steroids. The flavonoid class had - 1.24% of 5H-Dibenzo[c, f][1, 2] diazepine, 3, 8 dichloro-6,11-dihydro, at 3.702 RT, Alkaloid class has – 2.98% 2,6-Dibromobenzoquinone was detected at 4.403 RT, steroid – 2.98% Acetanilide, 2-chloro-4'-nitro- at 4.403 RT was obtained and Terpene – 2.05% of Methyl-beta.-[N-methylanilino]acrylate was detected at 4.719 RT, respectively. Most of the identified phytochemicals matched with synthetic drugs and confirmed the purpose of their applicability in traditional medicine. Considering the presence of numerous components and their correlation with conventional drugs, one can infer that this plant species has a good therapeutic application and can be utilized for health benefits

DRUDIT: web-based DRUgs DIscovery Tools to design small molecules as modulators of biological targets.

Abstract Motivation New in silico tools to predict biological affinities for input structures are presented. The tools are implemented in the DRUDIT (DRUgs DIscovery Tools) web service. The DRUDIT biological finder module is based on molecular descriptors that are calculated by the MOLDESTO (MOLecular DEScriptors TOol) software module developed by the same authors, which is able to calculate more than one thousand molecular descriptors. At this stage, DRUDIT includes 250 biological targets, but new external targets can be added. This feature extends the application scope of DRUDIT to several fields. Moreover, two more functions are implemented: the multi- and on/off-target tasks. These tools applied to input structures allow for predicting the polypharmacology and evaluating the collateral effects. Results The applications described in the article show that DRUDIT is able to predict a single biological target, to identify similarities among biological targets, and to discriminate different target isoforms. The main advantages of DRUDIT for the scientific community lie in its ease of use by worldwide scientists and the possibility to be used also without specific, and often expensive, hardware and software. In fact, it is fully accessible through the WWW from any device to perform calculations. Just a click or a tap can start tasks to predict biological properties for new compounds or repurpose drugs, lead compounds, or unsuccessful compounds. To date, DRUDIT is supported by four servers each able to execute 8 jobs simultaneously. Availability and implementation The web service is accessible at the www.drudit.com URL and its use is free of charge. Supplementary information Supplementary data are available at Bioinformatics online

A Multiple Classifier System Identifies Novel Cannabinoid CB2 Receptor Ligands

open access articleDrugs have become an essential part of our lives due to their ability to improve people’s health and quality of life. However, for many diseases, approved drugs are not yet available or existing drugs have undesirable side effects, making the pharmaceutical industry strive to discover new drugs and active compounds. The development of drugs is an expensive process, which typically starts with the detection of candidate molecules (screening) for an identified protein target. To this end, the use of high-performance screening techniques has become a critical issue in order to palliate the high costs. Therefore, the popularity of computer-based screening (often called virtual screening or in-silico screening) has rapidly increased during the last decade. A wide variety of Machine Learning (ML) techniques has been used in conjunction with chemical structure and physicochemical properties for screening purposes including (i) simple classifiers, (ii) ensemble methods, and more recently (iii) Multiple Classifier Systems (MCS). In this work, we apply an MCS for virtual screening (D2-MCS) using circular fingerprints. We applied our technique to a dataset of cannabinoid CB2 ligands obtained from the ChEMBL database. The HTS collection of Enamine (1.834.362 compounds), was virtually screened to identify 48.432 potential active molecules using D2-MCS. This list was subsequently clustered based on circular fingerprints and from each cluster, the most active compound was maintained. From these, the top 60 were kept, and 21 novel compounds were purchased. Experimental validation confirmed six highly active hits (>50% displacement at 10 μM and subsequent Ki determination) and an additional five medium active hits (>25% displacement at 10 μM). D2-MCS hence provided a hit rate of 29% for highly active compounds and an overall hit rate of 52%

2100 AI: Reflections on the mechanisation of scientific discovery

The pace of research is nowadays extremely intensive, with datasets and publications being published at an unprecedented rate. In this context data science, artificial intelligence, machine learning and big data analytics are providing researchers with new automatic techniques which not only help them to manage this flow of information but are also able to identify automatically interesting patterns and insights in this vast sea of information. However, the emergence of mechanised scientific discovery is likely to dramatically change the way we do science, thus introducing and amplifying serious societal implications on the role of researchers themselves, which need to be analysed thoroughly

Qualitative analysis of some bioactive components of methanolic leaf extract of M. citrifolia (Noni)

Medicinal plants offer endless opportunities for new drugs discovery due to their supremacy for the possession of phytochemicals compounds known for diverse antimicrobial activities. The world ever increasing demand for therapeutic drugs from natural products with particular interest in edible plants for safety purposes is now catching researchers’ attention. This study therefore aimed at determining the presence of some bioactive phytochemical components of methanolic leaf extract of M. citrifolia L. Qualitative screening of leaf extract has confirmed the existence of Tannins, steroids, saponins, flavonoids and alkaloids in the mixture. And these bioactive compounds correspond to phytochemicals with antimicrobial, nematicide, pesticidal, antioxidant, ant-inflammatory, cytotoxic, anti-allergy, and anti-carcinogenic properties (bioactive compounds) earlier documented by previous researchers

Evading innate immunity in nonviral mRNA delivery : don't shoot the messenger

In de field of non-viral gene therapy, in vitro transcribed (IVT) mRNA has emerged as a promising tool for the delivery of genetic information. Over the past few years it has become widely known the introduction of IVT mRNA into mammalian cells elicits an innate immune response which has favored mRNA use towards immunotherapeutic vaccination strategies. However, for non-immunotherapy related applications this intrinsic immune-stimulatory activity directly interferes with the aimed therapeutic outcome, as it can seriously compromise the expression of the desired protein. This review presents an overview of the immune-related obstacles that limit mRNA advance for non-immunotherapy related applications

Acoustically evoked potentials in two cephalopods inferred using the auditory brainstem response (ABR) approach

It is still a matter of debate whether cephalopods can detect sound frequencies above 400 Hz. So far there is no proof for the detection of underwater sound above 400 Hz via a physiological approach. The controversy of whether cephalopods have a sound detection ability above 400 Hz was tested using the auditory brainstem response (ABR) approach, which has been successfully applied in fish, crustaceans, amphibians, reptiles and birds. Using ABR we found that auditory evoked potentials can be obtained in the frequency range 400 to 1500 Hz (Sepiotheutis lessoniana) and 400 to 1000 Hz (Octopus vulgaris), respectively. The thresholds of S. lessoniana were generally lower than those of O. vulgaris