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Article

Structure-Based Discovery of MolPort-137: A Novel Autotaxin Inhibitor That Improves Paclitaxel Efficacy

by
Prateek Rai
1,2,†,
Christopher J. Clark
1,2,†,
Vandana Kardam
3,
Carl B. Womack
4,
Joshua Thammathong
2,
Derek D. Norman
5,
Gábor J. Tigyi
5,
Kevin Bicker
1,2,
April M. Weissmiller
1,4,
Kshatresh Dutta Dubey
3,* and
Souvik Banerjee
1,2,*
1
Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA
2
Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA
3
Department of Chemistry, Shiv Nadar Institution of Eminence, Delhi 201314, India
4
Department of Biology, Middle Tennessee State University, Murfreesboro, TN 37132, USA
5
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 37132, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(2), 597; https://doi.org/10.3390/ijms26020597
Submission received: 19 December 2024 / Revised: 8 January 2025 / Accepted: 10 January 2025 / Published: 12 January 2025
(This article belongs to the Special Issue Design, Synthesis and Biological Activity Evaluation of Kinase Inhibitors)
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Abstract

The autotaxin–lysophosphatidic acid receptor (ATX-LPAR) signaling axis is pivotal in various clinical conditions, including cancer and autoimmune disorders. This axis promotes tumorigenicity by interacting with the tumor microenvironment, facilitating metastasis, and conceding antitumor immunity, thereby fostering resistance to conventional cancer therapies. Recent studies highlight the promise of ATX/LPAR inhibitors in combination with conventional chemotherapeutic drugs to overcome some forms of this resistance, representing a novel therapeutic strategy. In the current study, we employed structure-based virtual screening, integrating pharmacophore modeling and molecular docking, to identify MolPort-137 as a novel ATX inhibitor with an IC50 value of 1.6 ± 0.2 μM in an autotaxin enzyme inhibition assay. Molecular dynamics simulations and binding free energy calculations elucidated the binding mode of MolPort-137 and its critical amino acid interactions. Remarkably, MolPort-137 exhibited no cytotoxicity as a single agent but enhanced the effectiveness of paclitaxel in 4T1 murine breast carcinoma cells and resensitized taxol-resistant cells to paclitaxel treatment, which highlights its potential in combination therapy.
Keywords: autotaxin; LPA signaling; virtual screening; molecular simulations; cancer therapy resistance; combination therapy autotaxin; LPA signaling; virtual screening; molecular simulations; cancer therapy resistance; combination therapy
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MDPI and ACS Style

Rai, P.; Clark, C.J.; Kardam, V.; Womack, C.B.; Thammathong, J.; Norman, D.D.; Tigyi, G.J.; Bicker, K.; Weissmiller, A.M.; Dubey, K.D.; et al. Structure-Based Discovery of MolPort-137: A Novel Autotaxin Inhibitor That Improves Paclitaxel Efficacy. Int. J. Mol. Sci. 2025, 26, 597. https://doi.org/10.3390/ijms26020597

AMA Style

Rai P, Clark CJ, Kardam V, Womack CB, Thammathong J, Norman DD, Tigyi GJ, Bicker K, Weissmiller AM, Dubey KD, et al. Structure-Based Discovery of MolPort-137: A Novel Autotaxin Inhibitor That Improves Paclitaxel Efficacy. International Journal of Molecular Sciences. 2025; 26(2):597. https://doi.org/10.3390/ijms26020597

Chicago/Turabian Style

Rai, Prateek, Christopher J. Clark, Vandana Kardam, Carl B. Womack, Joshua Thammathong, Derek D. Norman, Gábor J. Tigyi, Kevin Bicker, April M. Weissmiller, Kshatresh Dutta Dubey, and et al. 2025. "Structure-Based Discovery of MolPort-137: A Novel Autotaxin Inhibitor That Improves Paclitaxel Efficacy" International Journal of Molecular Sciences 26, no. 2: 597. https://doi.org/10.3390/ijms26020597

APA Style

Rai, P., Clark, C. J., Kardam, V., Womack, C. B., Thammathong, J., Norman, D. D., Tigyi, G. J., Bicker, K., Weissmiller, A. M., Dubey, K. D., & Banerjee, S. (2025). Structure-Based Discovery of MolPort-137: A Novel Autotaxin Inhibitor That Improves Paclitaxel Efficacy. International Journal of Molecular Sciences, 26(2), 597. https://doi.org/10.3390/ijms26020597

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