Repurposing drugs for the human dopamine transporter through WHALES descriptors-based virtual screening and bioactivity evaluation

Ding Luo; Zhou Sha; Junli Mao; Jialing Liu; Yue Zhou; Haibo Wu; Weiwei Xue

doi:10.1016/j.jpha.2025.101368

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Ding Luo, Zhou Sha, Junli Mao, Jialing Liu, Yue Zhou, Haibo Wu, Weiwei Xue. Repurposing drugs for the human dopamine transporter through WHALES descriptors-based virtual screening and bioactivity evaluation[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101368

Citation:

Ding Luo, Zhou Sha, Junli Mao, Jialing Liu, Yue Zhou, Haibo Wu, Weiwei Xue. Repurposing drugs for the human dopamine transporter through WHALES descriptors-based virtual screening and bioactivity evaluation[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101368

Citation:

Ding Luo, Zhou Sha, Junli Mao, Jialing Liu, Yue Zhou, Haibo Wu, Weiwei Xue. Repurposing drugs for the human dopamine transporter through WHALES descriptors-based virtual screening and bioactivity evaluation[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101368

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Repurposing drugs for the human dopamine transporter through WHALES descriptors-based virtual screening and bioactivity evaluation

doi: 10.1016/j.jpha.2025.101368

Ding Luo^a,
Zhou Sha^b,
Junli Mao^a,
Jialing Liu^a,
Yue Zhou^a,
Haibo Wu^{b
,
,},
Weiwei Xue^{a
,
,}

a. School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, China;
b. School of Life Sciences, Chongqing University, Chongqing, 401331, China

Funds:

This work was supported by the Natural Science Foundation of China (Grant No.: 21505009), the Natural Science Foundation of Chongqing, China (Grant No.: 2023NSCQ-MSX0140), and the Open Project of Central Nervous System Drug Key Laboratory of Sichuan Province, China (Grant No.: 230012-01SZ). We thank Prof. Xiaojun Yao at Macao Polytechnic University (Macao, China) for help and discussion on docking study.

Received Date: Dec. 07, 2024
Accepted Date: Jun. 11, 2025
Rev Recd Date: Apr. 21, 2025
Available Online: Jun. 18, 2025

Abstract

Abstract

Computational approaches, encompassing both physics-based and machine learning (ML) methodologies, have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities. The human dopamine (DA) transporter (hDAT) is the primary therapeutic target of numerous psychiatric medications. However, traditional hDAT-targeting drugs, which interact with the primary binding site, encounter significant limitations, including addictive potential and stimulant effects. In this study, we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape (WHALES) descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs. Initially, WHALES descriptors facilitated a similarity search, employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates. Consequently, from a compound library of 4,921 marketed and clinically tested drugs, we identified 27 candidate atypical inhibitors. Subsequently, ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates, while induced-fit docking (IFD) was performed to estimate their binding affinities. Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities. Among these, three exhibited significant inhibitory potency, with half maximal inhibitory concentration (IC₅₀) values of 0.753 μM, 0.542 μM, and 1.210 μM, respectively. Finally, molecular dynamics (MD) simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation. In conclusion, our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.
- Dopamine transporter,
- Drug repurposing,
- Molecular descriptors,
- Virtual screening,
- Molecular dynamics simulation

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References(78)

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