Computer-aided Drug Design on Glioblastoma Multiforme: Investigating Possible Inhibitors Against Factor H.

Introduction: Factor H acts as an inhibitory molecule in the complement activation pathways. Certain cancers express Factor H to escape the harmful features of the immune system. Here, we carried out high-throughput docking to determine a candidate inhibitor for Factor H-C3d binding. Hypothetically, the candidate inhibitor may serve as a possible additional therapeutic for certain cancers including glioblastoma multiforme (GBM). Method: Two approaches to computer-aided drug discovery were used. "Heuristic method" employed Factor H's binding pocket to construct counterpart molecules. "Comprehensive strategy" screened existing libraries for a potential inhibitor. Possible inhibitor molecules (target leads) were obtained from the Zinc20 database for the in silico, virtual screening purpose. Molecules that pass the Kd threshold were further analyzed by Molecular Dynamics simulations. Results: Three molecules were identified to be a suitable fit to inhibit Factor H in silico settings after a detailed investigation using both Heuristic and Comprehensive approaches. The molecule AQKQ had the smallest overall Root-mean-square deviation value. Molecule ARRE provided the best total energy (62,675 kJ/mol) for the system environment among the MD simulations performed. AQKQ-Factor H binding had the lowest energy with 24,852 kJ/mol. Wander will binding was shown to be higher for this molecule (23,724 kJ/mol). Following AQKQ, ARRE and THRS also displayed good binding energies (62,675 kJ/mol and 29,415 kJ/mol respectively). Conclusion: The findings of this study point to the possibility of using three compounds as a cancer therapeutic. Although the compounds demonstrated excellent binding abilities, their effectivity on cell level is still unclear. [ABSTRACT FROM AUTHOR]