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Virtual screening approaches for the identification of non-lipid autotaxin inhibitors
Abby L Parrill1, Uniqua Echols, Tran Nguyen
1Department of Chemistry, The University of Memphis, Memphis, TN 38152, USA. aparrill@memphis.edu
Abstract:
Autotaxin (ATX, NPP-2) catalyzes the conversion of lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA), a mitogenic cell survival factor that stimulates cell motility. The high expression of both ATX and receptors for LPA in numerous tumor cell types has produced substantial interest in exploring ATX as an anticancer chemotherapeutic target. ATX inhibitors reported to date are analogs of LPA, a phospholipid, and are more hydrophobic than is typical of orally bioavailable drugs. This study applied both structure-based and ligand-based virtual screening techniques with hit rates of 20% and 37%, respectively, to identify a promising set of non-lipid, drug-like ATX inhibitors. Structure-based virtual screening necessitated development of a homology model of the ATX catalytic domain due to the lack of structural information on any mammalian NPP family member. This model provided insight into the interactions necessary for ATX inhibition, and produced a suitably diverse training set for the development and application of binary QSAR models for virtual screening. The most efficacious compound identified in this study was able to completely inhibit ATX-catalyzed hydrolysis of 1 microM FS-3 (a synthetic, fluorescent LPC analog) at a 10 microM concentration.
Insights
Researchers identified novel, non-lipid drug-like inhibitors for autotaxin (ATX), an enzyme implicated in cancer. These compounds show promise as orally bioavailable anticancer therapeutics, offering a new avenue for drug development.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Autotaxin (ATX) enzyme activity is crucial for cell survival and motility.
- High ATX expression in tumors makes it a potential anticancer target.
- Existing ATX inhibitors are hydrophobic, limiting oral bioavailability.
Purpose of the Study:
- To identify novel, non-lipid, drug-like inhibitors of Autotaxin (ATX).
- To explore ATX as a target for anticancer chemotherapeutics with improved drug-like properties.
Main Methods:
- Employed structure-based and ligand-based virtual screening techniques.
- Developed a homology model of the ATX catalytic domain for structure-based screening.
- Utilized Quantitative Structure-Activity Relationship (QSAR) models for virtual screening.
Main Results:
- Achieved hit rates of 20% (structure-based) and 37% (ligand-based) virtual screening.
- Identified promising non-lipid ATX inhibitors with drug-like characteristics.
- The most effective compound inhibited ATX activity at a 10 microM concentration.
Conclusions:
- Novel non-lipid ATX inhibitors were successfully identified using virtual screening.
- These inhibitors represent a promising new class of potential anticancer drugs.
- The developed homology model and QSAR models are valuable tools for future drug discovery efforts.
