Idowu Olaposi Omotuyi Prof , Oyekanmi Nash Prof , Samuel Damilohun Metibemu Dr. , G. Chiamaka Iwegbulam , Olusina M. Olatunji , Emmanuel Agbebi , C. Olufunke Falade
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引用次数: 0
Abstract
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 (Kon/Koff) 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. 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- 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.
期刊介绍:
Computational Toxicology is an international journal publishing computational approaches that assist in the toxicological evaluation of new and existing chemical substances assisting in their safety assessment. -All effects relating to human health and environmental toxicity and fate -Prediction of toxicity, metabolism, fate and physico-chemical properties -The development of models from read-across, (Q)SARs, PBPK, QIVIVE, Multi-Scale Models -Big Data in toxicology: integration, management, analysis -Implementation of models through AOPs, IATA, TTC -Regulatory acceptance of models: evaluation, verification and validation -From metals, to small organic molecules to nanoparticles -Pharmaceuticals, pesticides, foods, cosmetics, fine chemicals -Bringing together the views of industry, regulators, academia, NGOs