Defining Known Drug Space by DFT based molecular descriptors. Virtual screening for novel Atg5-Atg16 complex inhibitors for autophagy modulation.

Matuszek, Anna and Reynisson, Johannes (2014) Defining Known Drug Space by DFT based molecular descriptors. Virtual screening for novel Atg5-Atg16 complex inhibitors for autophagy modulation. PhD thesis, UNSPECIFIED.

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Abstract or Summary

Section I The DFT study was performed on a collection of small molecule approved drugs, in order to study distributions of accurately predicted properties: dipole moment, polarisability, electron affinity and ionisation potential. The 95% of drugs was found within the individual limits of 10 D for DM, 68 Å3 for POL and respectively 9.0 and 2.0 eV for IP and EA. Three drug categories based on known oral absorption and bioavailability were established and compared. The high absorption boundaries were derived of 7.5 D for dipole moment, 45 Å3 for polarisability, 10 eV for ionisation potential and 2 eV for electron affinity, based on highest difference between high and low oral activity groups elimination. Within these limits, 88% of highly available drugs were found, whereas only 43% of low bioavailability drugs were present. The descriptors were then compared with mainstream descriptors’ performance. Section II The manipulation of autophagy could be a potential method of targeting various diseases and processes including cancer and neurodegradation. One of the most interesting targets within the autophagy cascade is the complex formed between Atg12 and Atg5-Atg16, which plays a crucial role in the formation of autophagosomes. The Atg5-Atg16 system is quite distinctive, with Atg16 bound to Atg5, only through non-covalent interactions. The two crucial interactions between the proteins occur with Atg16’s residues Phe46 and Arg35, which allow determination of active sites within the Atg5 protein. With the aim of finding potential inhibitors of complex formation, a virtual library consisting of 50,000 compounds was prepared and docked to both active pockets of the modelled complete structure of Atg5, using CCDC GOLD Suite. A series of virtual screening studies, followed by consensus scoring and visual inspection, led to the selection of 62 ligands (30 and 32 respectively for each pocket), from which 56 were sent for NCI-60 screening and 22 most promising ligands were experimentally evaluated at the University of Keele, UK, reporting two ligands showing an increased tendency for autophagy inhibition.

Item Type:Thesis (PhD)
Keywords that describe the item:medicinal computational chemistry, rule of five, molecular descriptors, drugs bioavailbility, authophagy inhibition
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Subjects:Q Science > QD Chemistry
Divisions:Schools > Centre for Science and Primary Industries
ID Code:5695
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Deposited On:17 Jan 2018 21:09
Last Modified:17 Jan 2018 21:09

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