Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR

Abstract

Topological polar surface area (TPSA), which makes use of functional group contributions based on a large database of structures, is a convenient measure of the polar surface area that avoids the need to calculate ligand 3D structure or to decide which is the relevant biological conformation or conformations. We demonstrate the utility of TPSA in 2D-QSAR for 14 sets of diverse pharmacological activity data. Even though a large pool of reports showing the importance of the classic 2D descriptors such as calculated logP (ClogP) and calculated molar refractivity (CMR) exists in the 2D-QSAR literature, this is the first report to demonstrate the value of TPSA as a relevant descriptor applicable to a large, structurally and pharmacologically diverse set of classes of compounds. We also address the limitations of applicability of this descriptor for 2D-QSAR analysis. We observed a negative correlation of TPSA with activity data for anticancer alkaloids, MT1 and MT2 agonists, MAO-B and tumor necrosis factor-alpha inhibitors and a positive correlation with inhibitory activity data for telomerase, PDE-5, GSK-3, DNA-PK, aromatase, malaria, trypanosomatids and CB2 agonists.

The Relevance of Polar Surface Area (PSA) in Rationalizing Biological Properties of Severalcis‐Diamminemalonatoplatinum(II) Derivatives

“…90 %), [44] but few studies have addressed the relevance of PSA in describing the cell penetration characteristics of antiproliferative drugs. [14,45] In the present study, we calculated total surface areas (CPK) and PSA values for all conformers of derivatives 1-8. Several variants of PSA calculations such as dynamic, topological, and fast PSA are incorporated in various software packages.…”

Synthesis and potent antistaphylococcal activity of some new 2-[4-(3,4-dimethoxyphenoxy)phenyl]-1,N-disubstituted-1H-benzimidazole-5-carboxamidines

“…A set of rules imposing limitations on log P, molecular weight, and the number of hydrogen bond donors and acceptors (known as the ''rule of 5'') introduced by Lipinski 17 (not more than 5 hydrogen bond donors, not more than 10 hydrogen bond acceptors, a molecular weight under 500 Da, and log P of less than 5) has become particularly popular. Another very useful parameter for prediction of drug candidate properties is the topological polar surface area (TPSA) 18 that is defined as a sum of surfaces of polar atoms (usually oxygens, nitrogens, and attached hydrogens) in a molecule. This parameter has been shown to correlate very well with ADME properties, including blood-brain barrier crossing tendency.…”

Leveraging chromatography based physicochemical properties for efficient drug design

“…While mostly used for barrier crossing prediction in an ADME context, TPSA has also been recently investigated as a descriptor for 2D-QSAR for diverse pharmacological activity data [74], as well as for active drug transport by multidrug resistance associated protein 1 (MRP1) [75].…”