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

ABSTRACT: 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.

SUBMITTER: Hsu KC

PROVIDER: S-EPMC5063375 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Hsu Kai-Cheng KC Wang Feng-Sheng FS

PloS one 20161013 10

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 ...[more]

PMID: 27736960

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Project description:IntroductionThe vaccine distribution for the COVID-19 is a multicriteria decision-making (MCDM) problem based on three issues, namely, identification of different distribution criteria, importance criteria and data variation. Thus, the Pythagorean fuzzy decision by opinion score method (PFDOSM) for prioritising vaccine recipients is the correct approach because it utilises the most powerful MCDM ranking method. However, PFDOSM weighs the criteria values of each alternative implicitly, which is limited to explicitly weighting each criterion. In view of solving this theoretical issue, the fuzzy-weighted zero-inconsistency (FWZIC) can be used as a powerful weighting MCDM method to provide explicit weights for a criteria set with zero inconstancy. However, FWZIC is based on the triangular fuzzy number that is limited in solving the vagueness related to the aforementioned theoretical issues.ObjectivesThis research presents a novel homogeneous Pythagorean fuzzy framework for distributing the COVID-19 vaccine dose by integrating a new formulation of the PFWZIC and PFDOSM methods.MethodsThe methodology is divided into two phases. Firstly, an augmented dataset was generated that included 300 recipients based on five COVID-19 vaccine distribution criteria (i.e., vaccine recipient memberships, chronic disease conditions, age, geographic location severity and disabilities). Then, a decision matrix was constructed on the basis of an intersection of the 'recipients list' and 'COVID-19 distribution criteria'. Then, the MCDM methods were integrated. An extended PFWZIC was developed, followed by the development of PFDOSM.Results(1) PFWZIC effectively weighted the vaccine distribution criteria. (2) The PFDOSM-based group prioritisation was considered in the final distribution result. (3) The prioritisation ranks of the vaccine recipients were subject to a systematic ranking that is supported by high correlation results over nine scenarios of the changing criteria weights values.ConclusionThe findings of this study are expected to ensuring equitable protection against COVID-19 and thus help accelerate vaccine progress worldwide.

Dataset Information

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

Publications

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

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