Fuzzy Decision Making Approach to Identify Optimum Enzyme Targets and Drug Dosage for Remedying Presynaptic Dopamine Deficiency

Model-based optimization approaches are valuable in developing new drugs for human metabolic disorders. The core objective in most optimal drug designs is positive therapeutic effects. In this study, we considered the effects of therapeutic, adverse, and target variation simultaneously. A fuzzy opti...

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Autores principales: Hsu, Kai-Cheng, Wang, Feng-Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063375/
https://www.ncbi.nlm.nih.gov/pubmed/27736960
http://dx.doi.org/10.1371/journal.pone.0164589
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author Hsu, Kai-Cheng
Wang, Feng-Sheng
author_facet Hsu, Kai-Cheng
Wang, Feng-Sheng
author_sort Hsu, Kai-Cheng
collection PubMed
description Model-based optimization approaches are valuable in developing new drugs for human metabolic disorders. The core objective in most optimal drug designs is positive therapeutic effects. In this study, we considered the effects of therapeutic, adverse, and target variation simultaneously. A fuzzy optimization method was applied to formulate a multiobjective drug design problem for detecting enzyme targets in the presynaptic dopamine metabolic network to remedy two types of enzymopathies caused by deficiencies of vesicular monoamine transporter 2 (VMAT2) and tyrosine hydroxylase (TH). The fuzzy membership approach transforms a two-stage drug discovery problem into a unified decision-making problem. We developed a nested hybrid differential evolution algorithm to efficiently identify a set of potential drug targets. Furthermore, we also simulated the effects of current clinical drugs for Parkinson’s disease (PD) in this model and tried to clarify the possible causes of neurotoxic and neuroprotective effects. The optimal drug design could yield 100% satisfaction grade when both therapeutic effect and the number of targets were considered in the objective. This scenario required regulating one to three and one or two enzyme targets for 50%–95% and 50%–100% VMAT2 and TH deficiencies, respectively. However, their corresponding adverse and target variation effect grades were less satisfactory. For the most severe deficiencies of VMAT2 and TH, a compromise design could be obtained when the effects of therapeutic, adverse, and target variation were simultaneously applied to the optimal drug discovery problem. Such a trade-off design followed the no free lunch theorem for optimization; that is, a more serious dopamine deficiency required more enzyme targets and lower satisfaction grade. In addition, the therapeutic effects of current clinical medications for PD could be enhanced in combination with new enzyme targets. The increase of toxic metabolites after treatment might be the cause of neurotoxic effects of some current PD medications.
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spelling pubmed-50633752016-11-04 Fuzzy Decision Making Approach to Identify Optimum Enzyme Targets and Drug Dosage for Remedying Presynaptic Dopamine Deficiency Hsu, Kai-Cheng Wang, Feng-Sheng PLoS One Research Article Model-based optimization approaches are valuable in developing new drugs for human metabolic disorders. The core objective in most optimal drug designs is positive therapeutic effects. In this study, we considered the effects of therapeutic, adverse, and target variation simultaneously. A fuzzy optimization method was applied to formulate a multiobjective drug design problem for detecting enzyme targets in the presynaptic dopamine metabolic network to remedy two types of enzymopathies caused by deficiencies of vesicular monoamine transporter 2 (VMAT2) and tyrosine hydroxylase (TH). The fuzzy membership approach transforms a two-stage drug discovery problem into a unified decision-making problem. We developed a nested hybrid differential evolution algorithm to efficiently identify a set of potential drug targets. Furthermore, we also simulated the effects of current clinical drugs for Parkinson’s disease (PD) in this model and tried to clarify the possible causes of neurotoxic and neuroprotective effects. The optimal drug design could yield 100% satisfaction grade when both therapeutic effect and the number of targets were considered in the objective. This scenario required regulating one to three and one or two enzyme targets for 50%–95% and 50%–100% VMAT2 and TH deficiencies, respectively. However, their corresponding adverse and target variation effect grades were less satisfactory. For the most severe deficiencies of VMAT2 and TH, a compromise design could be obtained when the effects of therapeutic, adverse, and target variation were simultaneously applied to the optimal drug discovery problem. Such a trade-off design followed the no free lunch theorem for optimization; that is, a more serious dopamine deficiency required more enzyme targets and lower satisfaction grade. In addition, the therapeutic effects of current clinical medications for PD could be enhanced in combination with new enzyme targets. The increase of toxic metabolites after treatment might be the cause of neurotoxic effects of some current PD medications. Public Library of Science 2016-10-13 /pmc/articles/PMC5063375/ /pubmed/27736960 http://dx.doi.org/10.1371/journal.pone.0164589 Text en © 2016 Hsu, Wang http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Hsu, Kai-Cheng
Wang, Feng-Sheng
Fuzzy Decision Making Approach to Identify Optimum Enzyme Targets and Drug Dosage for Remedying Presynaptic Dopamine Deficiency
title Fuzzy Decision Making Approach to Identify Optimum Enzyme Targets and Drug Dosage for Remedying Presynaptic Dopamine Deficiency
title_full Fuzzy Decision Making Approach to Identify Optimum Enzyme Targets and Drug Dosage for Remedying Presynaptic Dopamine Deficiency
title_fullStr Fuzzy Decision Making Approach to Identify Optimum Enzyme Targets and Drug Dosage for Remedying Presynaptic Dopamine Deficiency
title_full_unstemmed Fuzzy Decision Making Approach to Identify Optimum Enzyme Targets and Drug Dosage for Remedying Presynaptic Dopamine Deficiency
title_short Fuzzy Decision Making Approach to Identify Optimum Enzyme Targets and Drug Dosage for Remedying Presynaptic Dopamine Deficiency
title_sort fuzzy decision making approach to identify optimum enzyme targets and drug dosage for remedying presynaptic dopamine deficiency
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063375/
https://www.ncbi.nlm.nih.gov/pubmed/27736960
http://dx.doi.org/10.1371/journal.pone.0164589
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