Dihydroartemisinin binds human PI3K-β 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-β was computed using the MMPBSA method in comparison with the standard inhibitor (GD9). Kinetic parameter (K_on/K_off) was also evaluated for the complexes using adaptive sampling protocols and Markov state model analysis. p¹¹⁰-PI3K- β 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. K_on/K_off 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- β 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- β inhibitor.