PB0621 - Virtually screening for novel small molecule inhibitors against the conformational landscape of coagulation factor XIII activation-path

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Co-Author(s)

MI

Mohammad Mubasherrul Islam

Student
University of Bonn
Bonn, Nordrhein-Westfalen, Germany
Samhitha Urs Ramaraje Urs, MSc

PhD Student
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany
SS

Sneha Singh

Postdoctoral researcher
Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany
Haroon Javed, MSc

PhD student
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany
AP

Ajay Abhishek Paul George

Product Owner (Computer-Aided Drug Design Software)
BioSolveIT
Sankt Augustin, Nordrhein-Westfalen, Germany
DI

Diana Imhof

Professor
University of Bonn
Bonn, Nordrhein-Westfalen, Germany
Johannes Oldenburg

Professor, Chairman and Director
University Clinic Bonn AöR, Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany
Bonn, Nordrhein-Westfalen, Germany

Presenting Author(s)

Arijit Biswas, PD Dr (Biol)

Scientist
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany

Background: Although primarily known for the rare bleeding disorder its deficiency causes, coagulation Factor XIII (FXIII) is also known to play a major role in thrombosis making it a suitable and interesting pharmaceutical target for thrombotic events and directed inhibitor design. The activation of FXIII involves major structural/conformational changes, which provides a vast opportunity for computational screening for potential novel small molecule inhibitors against FXIII.

Aims: Our study aims to computationally screen FXIII activation-path structures for potential small molecule inhibitors of FXIII.

Methods: The Chembl, Pubchem and Binding database were searched for small molecule binding to FXIII (Figure 1.). Binding efficiency charts, Ki, Kd, Ro5 and Partition coefficient values integrated within the small molecule details were used as filters to narrow down only pharmacologically suitable molecules. The crystal structures of zymogenic/activated FXIIIA and previously reported FXIIIA activation path transition state structure-models (n=2) were loaded onto the SeeSar virtual-screening platform (BioSolveIT). Druggable pockets were identified for the structures on SeeSar and the family of small molecules screened from the medicinal chemistry databases were docked and poses within these binding pockets. The binding chemical space defined by the high affinity binding molecules/poses (nM binding affinity) were initially modified within the SeeSar to improve the molecules binding affinity or directly moved to the infiniSee chemical space navigation platform (BioSolveIT) to identify similar molecules across chemical spaces. Closest matches to target molecule were identified and re-docked on SeeSar platform on the FXIIIA structures and the promising ligands binding to functional areas of FXIII were identified based on binding affinity (Hyde scores).

Results: A total of 53 small molecules against the activation-path structures of FXIIIA.

Conclusion(s): We were able to identify a large number of small molecules binding with high affinity to FXIIIA. Their inhibitory capacity and specificity will now be tested on the bench.