Deep Learning in Drug Discovery and Medicine; Scratching the Surface.

The practice of medicine is ever evolving. Diagnosing disease, which is often the first step in a cure, has seen a sea change from the discerning hands of the neighborhood physician to the use of sophisticated machines to use of information gleaned from biomarkers obtained by the most minimally invasive of means. The last 100 or so years have borne witness to the enormous success story of allopathy, a practice that found favor over earlier practices of medical purgatory and homeopathy. Nevertheless, failures of this approach coupled with the omics and bioinformatics revolution spurred precision medicine, a platform wherein the molecular profile of an individual patient drives the selection of therapy. Indeed, precision medicine-based therapies that first found their place in oncology are rapidly finding uses in autoimmune, renal and other diseases. More recently a new renaissance that is shaping everyday life is making its way into healthcare. Drug discovery and medicine that started with Ayurveda in India are now benefiting from an altogether different artificial intelligence (AI)-one which is automating the invention of new chemical entities and the mining of large databases in health-privacy-protected vaults. Indeed, disciplines as diverse as language, neurophysiology, chemistry, toxicology, biostatistics, medicine and computing have come together to harness algorithms based on transfer learning and recurrent neural networks to design novel drug candidates, a priori inform on their safety, metabolism and clearance, and engineer their delivery but only on demand, all the while cataloging and comparing omics signatures across traditionally classified diseases to enable basket treatment strategies. This review highlights inroads made and being made in directed-drug design and molecular therapy.

Chinese Marine Materia Medica Resources: Status and Potential.

Chinese marine materia medica (CMMM) is a vital part of traditional Chinese medicine (TCM). Compared with terrestrial TCM, CMMM, derived from specific marine habitats, possesses peculiar chemical components with unique structures reflecting as potent pharmacological activities, distinct drug properties and functions. Nowadays, CMMM appears to be especially effective in treating such difficult diseases as cancers, diabetes, cardio-cerebrovascular diseases, immunodeficiency diseases and senile dementia, and therefore has become an important medicinal resource for the research and development of new drugs. In recent years, such development has attracted wide attention in the field of medicine. In this study, the CMMM resources in China were systematically investigated and evaluated. It was found that the historic experiences of Chinese people using CMMM have continuously accumulated over a period of more than 3600 years, and that the achievements of the research on modern CMMM are especially outstanding. By June 2015, 725 kinds of CMMMs from Chinese coastal sea areas have been identified and recorded, covering 1552 organisms and minerals. More than 3100 traditional prescriptions containing CMMMs have been imparted and inherited. However, the number of CMMMs is less than the 8188 terrestrial TCMs, from more than 12,100 medicinal terrestrial plants, animals and minerals. In the future, the research and development of CMMM should focus on the channel entries (TCM drug properties), compatibility, effective ingredients, acting mechanisms, drug metabolism and quality standard. This study reveals the high potential of CMMM development.

Truly personalised medicine: self-experimentation in medical discovery.

Biomedical research need not be carried out solely by 'Them': distant, dissociated, enormously costly institutions and companies. It can, and increasingly in the 21st century will, be carried out by 'Us', the informed non-professional. Conventional clinical trials treat humans with the same experimental model as laboratory rats - regarding them as mute, variable, unreliable material from which results must be obtained as fast as possible to maximise return on investment and patent life. The alternative is longer term, self-reported clinical studies of new treatments, based on the assumption that the experimenter is informed, intelligent and aware. A wide variety of new treatments for chronic disease are available, involving elements of diet, behaviour, environment and non-prescription medication as well as ethical pharmaceuticals, and previous experience suggests that they can be enormously effective. The key is objective, quantifiable measures of outcome. These can be achieved with over-the-counter diagnostics for a variety of parameters, as well as with self-built test systems, and careful and systematic observations of symptoms. Hypothesis generation is a key part of this process.

[New developments in neuromuscular blocking agents].

Curare was clinically used in a patient with acute appendicitis by Griffith and Johnson in January 1942. From the day on, the development of new muscle relaxants went on in the world. Since pancuronium was synthesized by Savage in 1964, it was widely used in clinical cases because it provided sufficient muscle relaxation during operation. At present, pancuronium, vecuronium and rocuronium are routinely used in the world. In the future, we expect development of new muscle relaxants with rapid onset, intermediate duration of action, rapid recovery and without side effects.

[Discovery strategy for effective and active constituents of Chinese material medica based on processes of metabolism and disposition in intra-body].

Chinese material medica is the natural therapeutic agent used under the guidance of the theories of traditional Chinese medicine. Its sources are mainly derive from plants, some derive from animals and minerals, and a few derive from chemical drugs and biologic products. It was made up into a colossal complexed system because it's diversity of biological sources, ecological environments, chemical structures, processing methods, processes of metabolism and disposition in intra-body, biological activity and clinical use, and involved a lot of scientific problems. The elucidation of the effective and active constituents is a basic and scientific problem to clarify complexed system of Chinese material medica. Along with research progressing of processes of metabolism and disposition of Chinese material medica in intra-body and metabonomics, a new and rapid-developing technology, the discovery strategy for effective and active constituents of Chinese material medica based on the processes of metabolism and disposition would be made up, which will provide a new methodology and pathway to clarify of complexed system of Chinese material medica.

New approaches for male fertility control: HE6 as an example of a putative target.

Reversible contraceptive methods for males are still not available. During the last few years several marketing studies have clearly shown that men and women would welcome a situation where men could assume responsibility for family planning. Schering AG and Organon are currently collaborating to develop a hormonal method for male fertility control based on the combination of etonogestrel as gestagenic component and testosterone undecanoate. To further optimize male contraceptives in terms of improved efficiency, rapid onset, reversibility, fewer side effects and a convenient method of application, a search for innovative non-hormonal approaches was started. During the last few years, numerous proteins were identified which play a specific role in male fertility. These proteins have first to fulfil a set of indication-specific criteria before a drug discovery process can be initiated. The most important criteria for a putative target protein are tissue-selective expression, crucial biological function in fertility, drugable properties and feasibility of assay development for high-throughput-screening and lead optimization. The G-protein-coupled receptor HE6 was selected as target and the above selection criteria were applied. HE6 displays a preferred epididymis-specific expression pattern and belongs to the superfamily of GPCRs, which are well known to be drugable with small molecules. A knockout mouse was generated which revealed an infertility phenotype with the onset occurring 6 weeks after initiation of spermatogenesis at the latest. Surprisingly, no epididymis-specific phenotype was observed. Instead, the reabsorption of testicular fluid along the efferent ducts was strongly affected. No further obvious side effects were observed in male or female mice. This study with HE6 exemplifies how targets for male contraception have to be validated before drug development can start.

Integrated approaches towards drug development from Ayurveda and other Indian system of medicines.

Biodiversity of natural resources has served not only for the primary human needs but also for health care, since time immemorial. The Indian subcontinent, with the history of one of the oldest civilization, harbors many traditional health care systems. Their development was supported by the diverse biodiversity in flora and fauna due to variations in geographical landscaping. Ayurveda, whose history goes back to 5000 b.c., is one of the ancient health care systems. The Ayurveda was developed through daily life experiences with the mutual relationship between mankind and nature. The ancient text of Ayurveda reports more than 2000 plant species for their therapeutic potentials. Besides Ayurveda, other traditional and folklore systems of health care were developed in the different time periods in Indian subcontinent, where more than 7500 plant species were used. According to a WHO estimate, about 80% of the world population relies on traditional systems of medicines for primary health care, where plants form the dominant component over other natural resources. Renewed interest of developing as well as developed countries in the natural resources has opened new horizons for the exploration of natural sources with the perspectives of safety and efficacy. The development of these traditional systems of medicines with the perspectives of safety, efficacy and quality will help not only to preserve this traditional heritage but also to rationalize the use of natural products in the health care. Until recent past, the nature was considered as a compendium for templates of new chemical entities (NCEs). The plant species mentioned in the ancient texts of these Ayurveda and other Indian systems of medicines may be explored with the modern scientific approaches for better leads in the health care.

The quest for bioisosteric replacements.

To help advance drug discovery projects, a new and validated search method is presented by which potential bioisosteric replacements can be retrieved from a database of more than 700,000 structural fragments. The heart of the search method is an optimized topological pharmacophore fingerprint which describes each fragment as a combination of attachment points, hydrogen bond donors and acceptors, hydrophobic centers, conjugated atoms, and non-hydrogen atoms. In the fingerprint the influence of the attachment point is enhanced by giving it extra weight relative to the other descriptors. The Euclidean distance has proven to be the optimum distance measure to compare the fingerprints in a database search. The performance of the pharmacophore fingerprint based search method has been validated using more than 2200 bioisosteric fragment pairs extracted in an unbiased procedure from the BIOSTER database. The true bioisosteric pairs have been compared with pairs of random fragments originating from the WDI database. Normalized by the standard deviation of the random pairs distance distributions, an excellent separation of true pairs from random pairs was obtained for R-group fragments (2.2 standard deviation units) as well as for linkers (2.6 units) and cores (2.6 units). The bioisoster search method has been implemented as an intranet application called IBIS and is now routinely used by Organon researchers.

Combining ethnopharmacology and virtual screening for lead structure discovery: COX-inhibitors as application example.

Virtual screening of large libraries of organic compounds combined with pharmacological high throughput screening is widely used for drug discovery in the pharmaceutical industry. Our aim was to explore the efficiency of using a biased 3D database comprising secondary metabolites from antiinflammatory medicinal plants as a source for the virtual screening. For this study pharmacophore models of cyclooxygenase I and II (COX-1, COX-2), key enzymes in the inflammation process, were generated with structure-based as well as common feature based modeling, resulting in three COX hypotheses. Four different multiconfomational 3D databases limited in molecular weight between 300 and 700 Da were applied to the screening in order to compare and analyze the obtained hit rates. Two of them were created in-house (DIOS, NPD). The database DIOS consists of 2752 compounds from phytochemical reports of antiinflammatory medicinal plants described by the ethnopharmacological source 'De material medica' of Pedanius Dioscorides, whereas NPD contains almost 80,000 compounds gathered arbitrarily from natural sources. In addition, two available multiconformational 3D libraries comprising marketed and development drug substances (DWI and NCI), mainly originating from synthesis, were used for comparison. As a test of the pharmacophore models' capability in natural sources, the models were used to search for known COX inhibitory natural products. This was achieved with some exceptions, which are discussed in the paper. Depending on the hypothesis used, DWI and NCI library searches produced hit rates in the range of 6.6% to 13.7%. A slight increase of the number of molecules assessed for binding was achieved with the database of natural products (NPD). Using the biased 3D database DIOS, however, the average increase of efficiency reached 77% to 133% compared to the hit rates resulting from WDI and NCI. The statistical benefit of a combination of an ethnopharmacological approach with the potential of computer aided drug discovery by in silico screening was demonstrated exemplified on the applied targets COX-1 and COX-2.

Modeling Physical-Chemical Properties of High Dilutions: an electrical conductivity study / Modelagem de propriedades físico-químicas das Altas Diluições: o estudo da condutividade elétrica

The most common way to perform succussions is to place a liquid preparation inside a glass vessel and beat it vigorously against a hard elastic surface, either manually or using a mechanical apparatus. This procedure has been assumed able to transfer mechanical energy to the molecular level, where it becomes available to perform chemical work. Such interpretation has been enforced by observed changes in the electrical conductivity (EC) of High Dilutions (HD) due to succussion. In order to address this question, we compared the electrical conductivity changes of HD prepared from Vincristine sulfate (VCR) samples with those of an inert solvent. Samples were produced through manual and mechanical succusions in order to observe the influence of bubbles production. The results confirmed the timing of EC changes but these were equivalent for VCR and solvent, except for VCR 1cH samples. Also, the production of bubbles does not affect the EC in an extent able to distinguish succussion procedures. We concluded that the physical-chemical properties of HD can be modeled by chemical and diffusive mechanisms typical of distilled water.(AU)

A maneira mais comum de realizar sucussões é manter uma preparação líquida dentro de um frasco de vidro, e agitá-la violentamente usando um dispositivo mecânico ou batendo-a, manualmente, contra um anteparo rígido, porém elástico. Este procedimento tem sido interpretado como um mecanismo capaz de transferir a energia mecânica da agitação, para níveis moleculares, onde ela se tornaria disponível para a realização de trabalho químico. Tal interpretação tem sido estimulada pela observação de alterações na condutividade elétrica (CE) de Altas Diluições (HD), devido à sucussão. Visando modelar esta questão, comparou-se a alteração da CE de amostras preparadas a partir de Sulfato de Vincristina (VCR) com amostras equivalentes (controle) preparadas apenas com o solvente água destilada. As amostras foram produzidas por sucussão mecânica e manual, a fimd e observar a influência da produção de bolhas. Os resultados confirma que a CE varia com o tempo, porém tais variações são equivalentes para VCR e controle, exceto para as amostras VCR 1cH. Também, a produção de bolhas não afeta a CE de forma a permitir usá-la para distinguir os diferentes procedimentos de sucussão. Concluimos que as propriedades físico-químicas da HDs podem ser modeladas por mecanismos químicos e difusivos, típicos para a água destilada.(AU)

Modeling physical-chemical properties of high dilutions: an electrical conductivity study / Modelagem de propriedades físico-químicas das altas diluições: o estudo da condutividade elétrica

The most common way to perform succussions is to place a liquid preparation inside a glass vessel and beat it vigorously against a hard elastic surface, either manually or using a mechanical apparatus. This procedure has been assumed able to transfer mechanical energy to the molecular level, where it becomes available to perform chemical work. Such interpretation has been enforced by observed changes in the electrical conductivity (EC) of High Dilutions (HD) due to succussion. In order to address this question, we compared the electrical conductivity changes of HD prepared from Vincristine sulfate (VCR) samples with those of an inert solvent. Samples were produced through manual and mechanical succusions in order to observe the influence of bubbles production. The results confirmed the timing of EC changes but these were equivalent for VCR and solvent, except for VCR 1cH samples. Also, the production of bubbles does not affect the EC in an extent able to distinguish succussion procedures. We concluded that the physical-chemical properties of HD can be modeled by chemical and diffusive mechanisms typical of distilled water.

A maneira mais comum de realizar sucussões é manter uma preparação líquida dentro de um frasco de vidro, e agitá-la violentamente usando um dispositivo mecânico ou batendo-a, manualmente, contra um anteparo rígido, porém elástico. Este procedimento tem sido interpretado como um mecanismo capaz de transferir a energia mecânica da agitação, para níveis moleculares, onde ela se tornaria disponível para a realização de trabalho químico. Tal interpretação tem sido estimulada pela observação de alterações na condutividade elétrica (CE) de Altas Diluições (HD), devido à sucussão. Visando modelar esta questão, comparou-se a alteração da CE de amostras preparadas a partir de Sulfato de Vincristina (VCR) com amostras equivalentes (controle) preparadas apenas com o solvente água destilada. As amostras foram produzidas por sucussão mecânica e manual, a fimd e observar a influência da produção de bolhas. Os resultados confirma que a CE varia com o tempo, porém tais variações são equivalentes para VCR e controle, exceto para as amostras VCR 1cH. Também, a produção de bolhas não afeta a CE de forma a permitir usá-la para distinguir os diferentes procedimentos de sucussão. Concluimos que as propriedades físico-químicas da HDs podem ser modeladas por mecanismos químicos e difusivos, típicos para a água destilada.

Diseño tecnológico de tabletas de Desipramina de liberación controlada / Technological design of controlled-release desipramine tablets

Se realizó un estudio preliminar con la finalidad de obtener tabletas de clorhidrato de desipramina (75 mg) de liberación controlada de lo cual no existen antecedentes de elaboración en la literatura universal. Se diseñaron 5 variantes tecnológicas de formulación, y se obtuvieron resultados muy alentadores al emplear como agentes retardantes dextrana técnica cubana e hidroxipropilmetilcelulosa (HPMC) en la masa y aglutinarla con una solución clorofórmica de alcohol cetílico, con lo cual se obtienen tabletas con excelentes propiedades físico--mecánicas y tecnológicas, y una satisfactoria cinética de disolución con un t100 porciento de aproximadamente 14 h de ensayo in vitro

Una estrategia para la selección sistemática de vehículos en el diseño de formas farmacéuticas líquidas homogéneas / Strategies for the systematic selection of vehicles in the design of liquid homogeneus pharmaceutical forms

La acumulación sistemática de datos fisicoquímicos es utilizable una y otra vez en el diseño de vehículos que cumplan las condiciones impuestas en el diseño y desarrollo de medicamentos. La puesta en práctica de la anterior metodología se ilustra en el presente artículo mediante un ejemplo de aplicación de la información fisicoquímica de sistemas solventes ternarios al diseño de un vehículo disolvente para una solución inyectable. La mezcla ternaria escogida, contituída por agua destilada, alcohol USP y propilenoglicol USP presenta restricciones en los valores de algunas de las propiedades fisicoquímicas, a causa de consideraciones biofarmacéuticas y tecnológicas. La selección de las mezclas que cumplen con las condiciones especificadas, se realiza utilizando las curvas isométricas en diagramas triangulares