Computational investigation of naturally occurring anticancer agents in regulating Hedgehog pathway proteins.

Embryonic development in humans is controlled by the Hedgehog pathway, which becomes inactive in mature tissues. Except for tissue maintenance and healing, activation of this pathway results in tumorigenesis with only a few exceptions. The drugs currently in use have shown no effectiveness in blocking the key proteins responsible for tumorigenesis. Therefore, it is crucial to find new inhibitors that can stop the abnormal activation of the pathway. A preliminary Insilco screening of naturally occurring compounds was carried out to identify potential inhibitors of the pathway. Docking of seventeen naturally occurring antitumorigenic compounds against the four key proteins of the regulatory proteins of the Hedgehog pathway using AutoDock v4.2.6 software was carried out. Liriodenine exhibited the strongest binding affinity towards three out of the four regulatory proteins (-7.61 kcal/mol with Smoothened, -8.14 kcal/mol with Patched-I, and -6.15 kcal/mol with Gli-II) of the Hedgehog pathway, whereas 2',4-dihydroxy-3-methoxychalcone displayed the highest binding affinity of -7.04 kcal/mol with the Sonic Hedgehog protein. Additional molecular dynamic simulation was conducted using Gromacs with Liriodenine and 2',4-dihydroxy-3-methoxy chalcone. Every protein-ligand complex underwent simulation using v5.1.4 software for a duration of 100 nanoseconds. The findings from the simulation indicate that Liriodenine and 2',4-dihydroxy-3-methoxy chalcone form a strong bond with their corresponding protein. Our findings show that the two aforementioned molecules have potential as new inhibitors of the pathway and should be further investigated in both invitro and in vivo experiments.