A Holistic In silico Approach to Develop Novel Inhibitors Targeting ErbB1 and ErbB2 Kinases

Purpose: To design a dual inhibitor of natural origin capable of targeting ErbB1 and ErbB2 kinases for the treatment of lung cancer.Method: Advanced In silico drug designing techniques were explored in this study. Sequence and structure analysis of ErbB1 and ErbB2 was followed by three dimensional (3D) pharmacophore. The generated model was used for molecular docking simulation studies for predicting the best natural dual inhibitors, the selected inhibitors were subjected to absorption, distribution, metabolism, excretion and toxicology (ADME/Tox) prediction.Results: The results confirmedfive phytochemicals, viz. hyoscyamide, cannabisin F, cochinchinenene D, cannabisin E, and heliotropamide and five FDA approved drugs namely fesoterodine, antrafenine, fluspirilene, posaconazole, and iloprost to be potential inhibitors of both ErbB1 and ErbB2. The shortlisted compounds from both the panels were showing better MolDock score than the two reference drugs (Lapatinib and Afatinib).Conclusion: The 3D pharmacophore modelling and molecular docking simulations gave us tencompounds that successfully exploited dual inhibition of ErbB1 and ErbB2. With 8 and 12 hydrogenbonds with ErbB1 and ErbB2 respectively cannabisin F showed best interaction of all.Keywords: Receptor tyrosine kinases, ErbB1, ErbB2, Natural products, Pharmacophore, Docking, Cancer therap

Development of long-range phase coherence on the Kondo lattice

Despite of many efforts, we still lack a clear picture on how heavy electrons emerge and develop on the Kondo lattice. Here we introduce a key concept named the hybridization bond phase and propose a scenario based on phase correlation to address this issue. The bond phase is a gauge-invariant quantity combining two onsite hybridization fields mediated by inter-site magnetic correlations. Its probabilistic distribution decays exponentially with site distance, from which a characteristic length scale can be extracted to describe the spatial correlation of Kondo hybridizations. Our calculations show that this correlation length grows logarithmically with lowering temperature at large Kondo coupling, and reveal a precursor pseudogap state with short-range phase correlation before long-range phase coherence is developed to form the Kondo insulating (or heavy electron) state at low temperatures. This provides a potential microscopic explanation of the two-stage hybridization proposed by recent pump-probe experiment and the logarithmic scaling in the phenomenological two-fluid model. Our work offers a novel theoretical framework to describe the phase-related physics in Kondo lattice systems.Comment: 9 pages, 5 figure