Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation.

Absolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.

Windows of opportunities and technological innovation in the Brazilian pharmaceutical industry.

The Brazilian pharmaceutical industry is heavily dependent on external sources of inputs, capital, and technology. However, the emergence of technological opportunities and the development of biotechnology and the decline of the patent boom and resulting advances by generic drugs have opened windows of opportunities for the local industry. The article examines the Brazilian industry's innovative behavior vis-à-vis these opportunities, showing that although the industry as a whole invests little in innovation, a few large Brazilian companies have expanded their market share and stepped up their investments in research and development, supported by public policies for innovation. Resumo: A indústria farmacêutica brasileira caracteriza-se pela grande dependência de fontes externas de insumos, capital e tecnologia. O surgimento de oportunidades tecnológicas, associadas ao desenvolvimento da biotecnologia e ao fim do boom das patentes com o consequente avanço dos medicamentos genéricos, entretanto, vem abrindo janelas de oportunidades para a indústria local. Este artigo examina o comportamento inovador da indústria brasileira à luz dessas oportunidades, revelando que, embora o conjunto da indústria mantenha baixos níveis de investimentos em inovação, um pequeno grupo de grandes empresas nacionais vem ampliando sua participação no mercado e intensificando seus investimentos em pesquisa e desenvolvimento, apoiados por políticas públicas de inovação.

Windows of opportunities and technological innovation in the Brazilian pharmaceutical industry / Ventanas de oportunidades e innovación tecnológica en la industria brasileña de medicamentos / Janelas de oportunidades e inovação tecnológica na indústria brasileira de medicamentos

Abstract: The Brazilian pharmaceutical industry is heavily dependent on external sources of inputs, capital, and technology. However, the emergence of technological opportunities and the development of biotechnology and the decline of the patent boom and resulting advances by generic drugs have opened windows of opportunities for the local industry. The article examines the Brazilian industry's innovative behavior vis-à-vis these opportunities, showing that although the industry as a whole invests little in innovation, a few large Brazilian companies have expanded their market share and stepped up their investments in research and development, supported by public policies for innovation.

Resumen: La industria farmacéutica brasileña se caracteriza por su gran dependencia de fuentes externas de insumos, capital y tecnología. El surgimiento de oportunidades tecnológicas, asociadas al desarrollo de la biotecnología, y al fin del boom de las patentes -con el consecuente avance de los medicamentos genéricos-, es paralelo a la apertura de ventanas de oportunidad para la industria local. Este artículo examina el comportamiento innovador de la industria brasileña a la luz de esas oportunidades, revelando que, aunque el conjunto de la industria mantenga bajos niveles de inversión en innovación, un pequeño grupo de grandes empresas nacionales está ampliando su participación en el mercado e intensificando sus inversiones en pesquisa y desarollo, apoyados por políticas públicas de innovación.

Resumo: A indústria farmacêutica brasileira caracteriza-se pela grande dependência de fontes externas de insumos, capital e tecnologia. O surgimento de oportunidades tecnológicas, associadas ao desenvolvimento da biotecnologia e ao fim do boom das patentes com o consequente avanço dos medicamentos genéricos, entretanto, vem abrindo janelas de oportunidades para a indústria local. Este artigo examina o comportamento inovador da indústria brasileira à luz dessas oportunidades, revelando que, embora o conjunto da indústria mantenha baixos níveis de investimentos em inovação, um pequeno grupo de grandes empresas nacionais vem ampliando sua participação no mercado e intensificando seus investimentos em pesquisa e desenvolvimento, apoiados por políticas públicas de inovação.

Needs-driven versus market-driven pharmaceutical innovation: the consortium for the development of a new medicine against malaria in Brazil.

The prevailing model for encouraging innovation based on patents and market-oriented raises at least two economic and ethical issues: it imposes barriers on individuals and developing countries governments' access to medicines by defining prices that do not match their income, and the unavailability of new or appropriate products to address the health problems of these populations. In the last decade, this scenario has undergone some changes due to the emergence of new actors, the contribution of aid resources, the introduction to the market of new products against neglected diseases, the development of new governmental healthcare policies and research programs, etc. One example of such initiatives is the Fixed-Dose Artesunate Combination Therapy (FACT) project consortium, which brought together institutions with different natures from both the North and the South, for the development of two antimalarial fixed-dose combinations recommended by the WHO - artesunate-amodiaquine (ASAQ) and artesunate-mefloquine (ASMQ). This paper proposes to describe and analyze the ASMQ consortium, which is the result of a new pharmaceutical development approach, based on a different paradigm - needs-driven instead of market-driven -, collaborative, with strategic participation of institutions from the South, funded by alternative resources (public and philanthropic). Thus, it represents an interesting object of study for bioethical debates on intellectual property and innovation, and its analysis is justified in light of the current debate on ways of stimulating needs-driven pharmaceutical innovation.

Cheminformatic models based on machine learning for pyruvate kinase inhibitors of Leishmania mexicana.

BACKGROUND: Leishmaniasis is a neglected tropical disease which affects approx. 12 million individuals worldwide and caused by parasite Leishmania. The current drugs used in the treatment of Leishmaniasis are highly toxic and has seen widespread emergence of drug resistant strains which necessitates the need for the development of new therapeutic options. The high throughput screen data available has made it possible to generate computational predictive models which have the ability to assess the active scaffolds in a chemical library followed by its ADME/toxicity properties in the biological trials. RESULTS: In the present study, we have used publicly available, high-throughput screen datasets of chemical moieties which have been adjudged to target the pyruvate kinase enzyme of L. mexicana (LmPK). The machine learning approach was used to create computational models capable of predicting the biological activity of novel antileishmanial compounds. Further, we evaluated the molecules using the substructure based approach to identify the common substructures contributing to their activity. CONCLUSION: We generated computational models based on machine learning methods and evaluated the performance of these models based on various statistical figures of merit. Random forest based approach was determined to be the most sensitive, better accuracy as well as ROC. We further added a substructure based approach to analyze the molecules to identify potentially enriched substructures in the active dataset. We believe that the models developed in the present study would lead to reduction in cost and length of clinical studies and hence newer drugs would appear faster in the market providing better healthcare options to the patients.

Brazilian pharmaceutical diplomacy: social democratic principles versus soft power interests.

Current debates concerning the rise of health diplomacy are polarized between competing international relations theories of realism, based on power politics, and constructivist approaches, which emphasize the norms, values, and identities shaping foreign policies. A case study of Brazil's health diplomacy over the past 10 years, focusing on issues related to pharmaceuticals, seeks to provide data to assess these theories. The country's intellectual property disputes, multilateral lobbying efforts, and foreign assistance programs are contrasted with those of the United States, Mexico, and other countries. Instead of viewing Brazilian efforts as a form of soft power, the evidence suggests that the origins of Brazil's involvement and continued efforts in this arena stem more from values based on human rights and social democratic principles. A close examination of domestic political considerations leads to a more nuanced understanding of the drivers behind a country's health diplomacy.

Global pharmaceutical development and access: critical issues of ethics and equity.

The article presents global data on access to pharmaceuticals and discusses underlying barriers. Two are highly visible: pricing policies and intellectual property rights; two are less recognized: the regulatory environment and scientific and technological capacities. Two ongoing transitions influence and even distort the problem of universal access to medications: the epidemiologic transition to an increasing burden of chronic non-communicable diseases; and the growing role of biotechnology products (especially immunobiologicals) in the pharmacopeia. Examples from Cuba and Brazil are used to explore what can and should be done to address commercial, regulatory, and technological aspects of assuring universal access to medications.

El artículo presenta datos globales sobre el acceso a los productos farmacéuticos y examina las barreras subyacentes. Dos de ellas son claramente visibles: las políticas de fi jación de precios, y los derechos de propiedad intelectual; otras dos son menos reconocidas: el medio regulatorio y las capacidades científi cas y tecnológicas. Dos transiciones en curso infl uencian e incluso distorsionan el problema del acceso universal a los medicamentos: la transición epidemiológica hacia una carga cada vez mayor de enfermedades crónicas no transmisibles; y el creciente papel de los productos biotecnológicos (especialmente los productos inmunobiológicos) en la farmacopea. Se utilizan los ejemplos de Cuba y Brasil para explorar lo que puede y debe hacerse para solventar los aspectos comerciales, regulatorios y tecnológicos de garantizar el acceso universal a los medicamentos. PALABRAS CLAVE Biotecnología, productos biológicos, ensayos clínicos, costo de los medicamentos, economía, farmacéutico, preparaciones farmacéuticas, propiedad intelectual, patentes, acceso a la atención en salud, salud global, Cuba, Brasil.

Patenting bioactive molecules from biodiversity: the Brazilian experience.

The use of natural compounds from biodiversity, as well as ethnobotanical knowledge, for the development of new drugs is the gate leading to support the conservation of natural resources in developing countries. Recent technological advances and the development of new methods are revolutionizing the screening of natural products and offer a unique opportunity to replace natural products as major source of drug leads. Over the past decades, the Brazilian government established a legislation aiming to grant patent protection in all technological fields. The Convention on Biological Diversity, an international agreement that recognizes the sovereign rights of States over their natural resources, and the Brazilian legislation (Decreto n degree 2186-12/01) set for legislative, administrative or policy measures regarding the share of research and product development benefits could be the key for progress in issues related to rational employment of the Brazilian biodiversity and economy, but are far from being effective. Based on literature review, this article provides a brief description of the Brazilian legislation policy regarding intellectual property and biodiversity access, places natural drug discovery in context, analyzes patent cases and highlights critical key issues responsible for the drawback of the whole process that has a direct impact on industrial and research development, nature protection and benefit share with our society.

[Competition and prices in the Mexican pharmaceutical market]. / Competencia y precios en el mercado farmacéutico mexicano.

The forms of market competition define prices. The pharmaceutical market contains submarkets with different levels of competition; on the one hand are the innovating products with patents, and on the other, generic products with or without trade names. Innovating medicines generally have monopolistic prices, but when the patents expire prices drop because of competition from therapeutic alternatives. The trade name makes it easier to maintain monopolistic prices. In Mexico, medicine prices in the private market are high--according to aggregated estimates and prices for specific medicines--which reflect the limitations of pharmaceutical market competition and the power of the trade name. The public segment enjoys competitive prices using the WHO strategy for essential medicines on the basis of the Essential List.

[Healthy pharmaceutical policy]. / Política farmacéutica saludable.

Today, the pharmaceutical industry is experiencing a profound transition. Globalization and technological advancement represent the principal pressures for change in the market, where it is increasingly more difficult for this type of industry to efficiently recoup the growing cost of innovation. Mexico needs to analyze the policy implications of these change factors and promote, in the pharmaceutical market, policies that maximize health gains on invested resources. Pharmaceutical policy offers a rare example for a complementary approach between a sound health policy and an efficient economic policy; that is, a "healthy pharmaceutical policy."

The prince and the pauper. A tale of anticancer targeted agents.

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater.

Política farmacéutica saludable / Healthy pharmaceutical policy

Hoy en día, la industria farmacéutica se encuentra en una transición profunda. La globalización y el avance tecnológico representan las principales presiones de cambio para un mercado mundial de medicamentos donde a este tipo de industria le resulta cada vez más difícil recuperar de forma eficiente los costos crecientes de la innovación. México debe analizar las implicaciones en el ámbito político de estos factores de cambio y promover, en el mercado de medicamentos, una política que incremente al máximo las ganancias de salud de los recursos invertidos. La política de medicamentos ofrece un raro ejemplo de complementariedad entre una buena política de salud y una política económica eficiente, es decir, una "política farmacéutica saludable".

Today, the pharmaceutical industry is experiencing a profound transition. Globalization and technological advancement represent the principal pressures for change in the market, where it is increasingly more difficult for this type of industry to efficiently recoup the growing cost of innovation. Mexico needs to analyze the policy implications of these change factors and promote, in the pharmaceutical market, policies that maximize health gains on invested resources. Pharmaceutical policy offers a rare example for a complementary approach between a sound health policy and an efficient economic policy; that is, a "healthy pharmaceutical policy."

Competencia y precios en el mercado farmacéutico mexicano / Competition and prices in the Mexican pharmaceutical market

Las formas que asume la competencia en el mercado definen el nivel de precios. El mercado farmacéutico contiene submercados con diferente grado de competencia; por un lado existen productos innovadores con patente y, por el otro, genéricos con marca comercial o sin ella. Por lo general, los medicamentos innovadores con patente tienen precios monopólicos, pero a su vencimiento éstos bajan al enfrentar la competencia de alternativas terapéuticas. La marca permite conservar las rentas económicas del monopolio. En México los precios de los medicamentos en el mercado privado son elevados, de acuerdo con las estimaciones agregadas y para medicamentos específicos, lo cual refleja las limitaciones de la competencia en el mercado y el poder de la marca comercial. En el segmento público se obtienen precios competitivos con la estrategia de los medicamentos esenciales de la Organización Mundial de la Salud, con base en el listado de productos del Cuadro Básico.

The forms of market competition define prices. The pharmaceutical market contains submarkets with different levels of competition; on the one hand are the innovating products with patents, and on the other, generic products with or without trade names. Innovating medicines generally have monopolistic prices, but when the patents expire prices drop because of competition from therapeutic alternatives. The trade name makes it easier to maintain monopolistic prices. In Mexico, medicine prices in the private market are high -according to aggregated estimates and prices for specific medicines- which reflect the limitations of pharmaceutical market competition and the power of the trade name. The public segment enjoys competitive prices using the WHO strategy for essential medicines on the basis of the Essential List.