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.

Regioselective Synthesis, Molecular Descriptors of (1,5‐Disubstituted 1,2,3‐Triazolyl)Coumarin/Quinolone Derivatives and Their Docking Studies against Cancer Targets

“…First, the DM of tcd and tqd show a decreasing trend from 5b to 5i (Figure a) indicated that the charge distribution in 5b and 5i are highest and lowest, respectively. The DM of tcd and tqd has been around the earlier mean (i. e. 4.6; dotted line in Figure a), which are much below than the upper‐limit i. e. 10D . Second, we have computed polarizability and higher order hyperpolarizability (such as β and γ ) for tcd and tqd.…”

“…Earlier, adiabatic IP and adiabatic EA were used as descriptor for understanding drug‐likeness of clinically approved drugs . Here, we have also computed these properties for tcd and tqd (Figure f and 4g) and compared with earlier mean (dotted line in Figure f and 4g, respectively) and range values .…”

“…We have two classes of compounds, triazolyl coumarin derivatives (tcd) and triazolyl quinolone derivatives (tqd). These QM‐parameters of our compounds are computed using B3LYP/6‐311G (d,p) level of theory in Gaussian Software as earlier ,…”

A Chemometric Analysis of Compounds from Native New Zealand Medicinal Flora

“…Some of the studied molecular descriptors (molecular weight, lipophilicty (Log P), the number of hydrogen bond donors, hydrogen bond acceptors and rotatable bonds, polar surface area) of the molecule have been extensively used in the assessment of a molecules’ suitability to be considered as a drug . While the dipole moment, polarizability, ionization potential and water solubility (Log S) of the compound has been less used, but are recently increasingly being examined …”

“…The compound types all had similar mean values for ionization potentials with all types having means between 8.6 and 10 eV with the exception of alkanes (mean ionization potential=11.0 eV). Ionization potential has been shown to reflect the redox stability of compounds, hence their ease of metabolism in the body …”