Dihydroartemisinin binds human PI₃K- affinity pocket and forces flat conformation in P-loop MET⁷⁸³: A molecular dynamics study

Artemisinin and its semi-synthetic derivatives are not only indicated for malaria but also cancer, inflammatory and autoimmune diseases. Its inflammatory and immunosuppressive target is PI3K/AKT pathways. The structural and kinetic aspect of the PI3K inhibition was investigated in the current study using computational approaches. Binding energies of dihydroartemisinin (DHA) to p110-PI3K-beta was computed using the MMPBSA method in comparison with the standard inhibitor (GD9). Kinetic parameter (Kon/Koff) was also evaluated for the complexes using adaptive sampling protocols and Markov state model analysis. p110-PI3K-beta dynamics and community network analysis were also performed following conventional Molecular dynamics simulation. The results showed-63.99 +/- 1.53 and-74.14 +/- 3.47 (Kj/mol) binding energies for DHA and GD9 respectively. Kon/Koff estimates for DHA and GD9 are 12.4, and 2.13 (M-1) respectively. Analysis of the trajectories showed that DHA selectively partitions into p110-PI3K- beta affinity pocket, forces open conformation, and kept catalytic pocket-M783 in a flat conformation whilst forcing large displacement around the C2-domain. In conclusion, DHA is a high affinity (slow-binding, slow-dissociating), flat-conformation p110-PI3K-beta inhibitor.