Modeling the pharmacodynamics of passive membrane permeability

Small molecule permeability through cellular membranes is critical to a better understanding of pharmacodynamics and the drug discovery endeavor. Such permeability may be estimated as a function of the free energy change of barrier crossing by invoking the barrier domain model, which posits that permeation is limited by passage through a single “barrier domain” and assumes diffusivity differences among compounds of similar structure are negligible. Inspired by the work of Rezai and co-workers (JACS 128:14073–14080, 2006), we estimate this free energy change as the difference in implicit solvation free energies in chloroform and water, but extend their model to include solute conformational affects. Using a set of eleven structurally diverse FDA approved compounds and a set of thirteen congeneric molecules, we show that the solvation free energies are dominated by the global minima, which allows solute conformational distributions to be effectively neglected. For the set of tested compounds, the best correlation with experiment is obtained when the implicit chloroform global minimum is used to evaluate the solvation free energy difference

Selective effect of cell membrane on synaptic neurotransmission

Atomistic molecular dynamics simulations were performed with 13 non-peptidic neurotransmitters (NTs) in three different membrane environments. The results provide compelling evidence that NTs are divided into membrane-binding and membrane-nonbinding molecules. NTs adhere to the postsynaptic membrane surface whenever the ligand-binding sites of their synaptic receptors are buried in the lipid bilayer. In contrast, NTs that have extracellular ligand-binding sites do not have a similar tendency to adhere to the membrane surface. This finding is a seemingly simple yet important addition to the paradigm of neurotransmission, essentially dividing it into membrane-independent and membrane-dependent mechanisms. Moreover, the simulations also indicate that the lipid composition especially in terms of charged lipids can affect the membrane partitioning of NTs. The revised paradigm, highlighting the importance of cell membrane and specific lipids for neurotransmission, should to be of interest to neuroscientists, drug industry and the general public alike.Peer reviewe

Experiência Profissionalizante na vertente de Farmácia Comunitária, Hospitalar e Investigação

O estágio curricular, realizado no final do Mestrado Integrado em Ciências Farmacêuticas, apresenta-se como a oportunidade de aplicar os conhecimentos adquiridos ao longo dos 5 anos de estudo, constituindo uma importante aproximação à prática profissional e uma oportunidade de contato com as tarefas e atividades desenvolvidas pelo Farmacêutico. De forma igual à realização do estágio curricular, este relatório encontra-se organizado em três partes distintas: a primeira referente à componente de investigação desenvolvida, a segunda referente ao estágio em Farmácia Comunitária, e por último, a terceira referente ao estágio em Farmácia Hospitalar. No primeiro capítulo encontra-se a componente de investigação desenvolvida, intitulada: "Predição in silico da permeabilidade intrínseca determinada pelo ensaio in vitro Double-Sink PAMPA utilizando redes neuronais artificiais". Os ensaios in vitro são imprescindíveis na descoberta e desenvolvimento de novos fármacos. O PAMPA, Parallel Artificial Membrane Permeability Assay, é um exemplo de grande utilidade nos processos de screening in vitro da permeabilidade intestinal, permitindo prioritizar as moléculas com propriedades mais favoráveis. Apesar da utilidade dos modelos in vitro, é hoje consensual a necessidade do desenvolvimento e aplicação prévia de modelos in silico nas fases iniciais de descoberta de fármacos. Os ensaios in silico, embora menos exatos que os in vitro, possibilitam um screening rápido, a baixo custo, de milhares de moléculas, permitindo selecionar as mais promissoras para posterior avaliação in vitro. Neste âmbito, as redes neuronais artificiais têm vindo a assumir um papel relevante na avaliação farmacológico in silico. Desta forma, com este trabalho pretende-se desenvolver um modelo computacional (in silico) para a predição da permeabilidade intrínseca (Po) de compostos utilizando redes neuronais artificiais (ANNs), construído com observações feitas em 273 moléculas, utilizando apenas descritores calculados in silico. No segundo capítulo encontra-se descrito o estágio curricular em Farmácia Comunitária. Este estágio foi realizado na Farmácia São Cosme, na Covilhã, entre os dias 4 de fevereiro e 3 de maio de 2013. Sob a orientação do Dr. Carlos Tavares e toda a equipa presente na Farmácia, foi me dada a oportunidade de integrar uma equipa de trabalho e acompanhar e experienciar todas as atividades desenvolvidas pelo Farmacêutico neste âmbito profissional. Com este relatório pretende-se descrever o funcionamento de uma Farmácia Comunitária, bem como as tarefas e responsabilidades do farmacêutico nesta. Por último, no terceiro capítulo encontra-se descrito o estágio curricular em Farmácia Hospitalar, realizado nos Serviços Farmacêuticos Hospitalares do Centro Hospitalar Cova da Beira, entre os dias 6 de maio e 21 de junho de 2013. Sob orientação da Prof.ª Olímpia Fonseca e colegas presentes nas diversas áreas, tive a oportunidade de participar nas diversas tarefas e atividades desenvolvidas neste serviço. Com este relatório pretende-se assim descrever as atividades que acompanhei e realizei, bem como as competências técnicas que adquiri.The final traineeship, held at the end of the Pharmaceutical Sciences master's degree program, presents itself as an opportunity to apply the knowledge gained over the five years of study, as well as it is an important approach to the professional practice and a chance to observe the tasks and activities developed by the Pharmacist. Similarly to the traineeship, this report is organized into three distinct parts: the first related wit h the research component, the second related with Community Pharmacy traineeship, and lastly, the third related with the Hospital Pharmacy traineeship. The first chapter describes the research component developed, entitled: "In silico prediction of the in vitro intrinsic permeability determined in Double-Sink PAMPA by using artificial neural networks". In vitro assays are essential in the discovery and development of new drugs. PAMPA, Parallel Artificial Membrane Permeability Assay, is an example of great interest for screening of intestinal permeability, allowing the prioritization of molecules with more favorable properties. Despite the usefulness of in vitro models, it is now generally agreed to the need for development and prior application of in silico model in the early stages of drug discovery. In silico assays, although less accurate than the in vitro assays, are powerful tools for a rapid virtual screening of thousands of compounds at low cost, allowing to select the most promising for further in vitro evaluation. In this context, artificial neural networks have come to play a relevant role in the in silico evaluation of pharmacological properties. Thus, this work aims to develop a computational model (in silico) to predict the intrinsic permeability (Po) of compounds using artificial neural networks (ANNs), built with observations made in 273 molecules, using only in silico calculated descriptors. The second chapter describes the traineeship in Community Pharmacy. This traineeship was conducted in Pharmacy São Cosme, in Covilhã, between February 4th and May 3 r d, 2013. Under the guidance of Dr. Carlos Tavares and the whole team present in the pharmacy, I was given the opportunity to join a team and experience all activities carried out by the pharmacist in this professional field. This report aims to describe the working of a Community Pharmacy, as well as the tasks and responsibilities of the Pharmacist in it. Finally, the third chapter describes the traineeship in Hospital Pharmacy, conducted in the Pharmaceutical Services of Centro Hospitalar Cova da Beira, between May 6th and June 21st of 2013. Under the guidance of Prof.ª Olímpia Fonseca and coworkers assigned to the different areas of the Pharmaceutical Services, I was given the opportunity to participate in various tasks and activities developed in this service. This report aims to describe the activities performed as well as the technical skills acquired