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Identifying new clotting factor XIa inhibitors in virtual high-throughput screens using PCA-GA-SVM models and
Jonathan J Chen1, Lyndsey N Schmucker2, Donald P Visco2
1Dept. of Biology, The University of Akron, 302 Buchtel Common, Akron, OH, 44325.
Abstract:
Blood Clotting Factor XI is an important actor in the clotting mechanism: it activates downstream zymogen involved in the clotting process. It can be targeted for activation or inhibition depending on treatment goals to enhance or inhibit clotting. In terms of antithrombosis treatment, Factor XI has emerged as a promising target to focus on. In this work, an iterative virtual high-throughput screening pipeline was proposed that can supplement current efforts to find inhibitors. The first iteration identified 11 compounds to test with 3 active for a hit-rate of 27.3%. The second iteration of the pipeline identified another 11 compounds to test with 7 active for a hit-rate of 63.6%. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1553-1565, 2018.
Insights
An iterative virtual screening pipeline identified inhibitors for blood clotting Factor XI, a key target for antithrombosis treatments. The pipeline achieved a 63.6% hit rate in its second iteration, improving drug discovery efficiency.
Area of Science:
- Biotechnology and Biomedical Engineering
- Biochemistry and Molecular Biology
- Pharmacology and Drug Discovery
Background:
- Blood Clotting Factor XI plays a crucial role in the coagulation cascade.
- Factor XI is a promising therapeutic target for antithrombosis treatments.
- Current methods for identifying Factor XI inhibitors can be supplemented by computational approaches.
Purpose of the Study:
- To develop and validate an iterative virtual high-throughput screening (vHTS) pipeline for identifying Factor XI inhibitors.
- To assess the efficiency and hit rate of the vHTS pipeline over multiple iterations.
Main Methods:
- An iterative vHTS pipeline was designed and implemented.
- Computational screening of compound libraries was performed.
- Active compounds were identified and validated through testing.
Main Results:
- The first iteration of the pipeline identified 11 compounds, with 3 confirmed as active (27.3% hit rate).
- The second iteration yielded 11 additional compounds, 7 of which were active (63.6% hit rate).
- The iterative approach significantly improved the hit rate in subsequent screening rounds.
Conclusions:
- The proposed iterative vHTS pipeline is effective in identifying blood clotting Factor XI inhibitors.
- This computational approach can enhance the efficiency of drug discovery for antithrombotic agents.
- The improved hit rate demonstrates the value of iterative refinement in virtual screening.
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