title: Defining Known Drug Space Using DFT.
abstract: A density functional theory (DFT) study was performed on a collection of clinically approved drugs, or Known Drug Space (KDS), to determine the statistical distribution of four properties: dipole moment (DM), polarisability (POL), ionisation potential (IP) and electron affinity (EA). The DM and POL are linked to cell permeability of drugs whereas IP and EA reflect their redox stability thus ease of metabolism. A benchmarking exercise showed a good correlation between experimental values and their predicted counterparts. It was found that KDS occupies the volume of chemical space defined by: DM≤10 D, POL≤68 Å(3) , IP 6.0-9.0 V and EA-1.5-2.0 eV. Only 16 % of the drugs are outside one or more of these parameters. Three categories based on known oral absorption and bioavailability (low/medium/high) were established and compared. Predominately, drugs designated as 'low' were found outside the established parameters. The properties were compared with mainstream molecular descriptors and a strong correlation was seen for POL to MW (r(2) =0.899), which can explain the success of the latter since POL reflects the ability of molecules to interact with polar and non-polar environments such as water and interior of a membrane.
authors: School of Chemical Sciences, University of Auckland, New Zealand, Private Bag 92019, Auckland 1142, New Zealand, Tel. 64-9-373-7599 ext. 83746, Fax. 64-9-373-7422.
authors: Anna M
authors: AM
authors: Matuszek
authors: School of Chemical Sciences, University of Auckland, New Zealand, Private Bag 92019, Auckland 1142, New Zealand, Tel. 64-9-373-7599 ext. 83746, Fax. 64-9-373-7422. j.reynisson@auckland.ac.nz.
authors: Jóhannes
authors: J
authors: Reynisson
mesh_terms: D055808:Drug Discovery; D006860:Hydrogen Bonding; D015394:Molecular Structure; D004364:Pharmaceutical Preparations; D011789:Quantum Theory
chemical_list: D004364:Pharmaceutical Preparations
keywords: B3LYP; chemical space; chemoinformatics and drug discovery; molecular descriptors