Structure-Based Discovery of MolPort-137: A Novel Autotaxin Inhibitor That Improves Paclitaxel Efficacy.
Prateek Rai, Christopher J Clark, Vandana Kardam, Carl B Womack, Joshua Thammathong, Derek D Norman, Gábor J Tigyi, Kevin Bicker, April M Weissmiller, Kshatresh Dutta Dubey, Souvik Banerjee
Author Information
Prateek Rai: Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA. ORCID
Christopher J Clark: Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA.
Vandana Kardam: Department of Chemistry, Shiv Nadar Institution of Eminence, Delhi 201314, India.
Carl B Womack: Department of Biology, Middle Tennessee State University, Murfreesboro, TN 37132, USA.
Joshua Thammathong: Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA.
Derek D Norman: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 37132, USA.
Gábor J Tigyi: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 37132, USA. ORCID
Kevin Bicker: Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA.
April M Weissmiller: Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA. ORCID
Kshatresh Dutta Dubey: Department of Chemistry, Shiv Nadar Institution of Eminence, Delhi 201314, India. ORCID
Souvik Banerjee: Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA. ORCID
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 IC 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.
