QSAR Analysis and ADMET Study on 3, 5-Disubstituted Oxadiazole Derivatives as Anticancer Agents

Abstract

Two-dimensional Quantitative Structure Activity Relationship (QSAR) study was performed on a series of 3-(aryl)-5-aryl amino-1,2,4-Oxadiazoles in order to establish the quantitative relationship between physicochemical properties and antiproliferative activity using Molecular Design Suite (VLifeMDS). The data set for this investigation consisted of 20 chemicals, which were divided into training and test set using the sphere exclusion (SE) algorithm and manual selection techniques. The QSAR models were constructed using the PLSR approach and the stepwise (SW) forward-backward variable selection method. Statistically significant QSAR models were generated. Most significant model generated (Model-1), explains 88% (r2 = 0.8229) of the overall variance in the training set as well as it has internal (q2) and external (pred_r2) predicative ability of 62% (q2 = 0.6202) and 76% (pred_r2 = 0.7566), respectively. The QSAR model (Model-1) indicates descriptors SKMostHydrophilic, T_C_N_7 and AveragePotential contributing 40%, 32% and 28 %, respectively to biological activity. Pharmacokinetic and Toxicity [Absorption, distribution, metabolism, excretion and toxicity (ADMET)] properties, drug likeness (DL) and drug score (DS) were also computed. All the compounds show good NR-AR score > 0.7, indicating that they interact with androgen receptor and may be effective in AR-dependent prostate cancer and other androgen related diseases. DL and DS score of most active compound 2t was found 0.23 and 0.51, respectively. Furthermore, DL score of Compounds 2g, 2m, 2k and 2s has been found 2.6, 1.28, 0.88 and 0.77, respectively and are relatively safe as far as toxicity is concerned. Lipinski rule of five for all compounds met under acceptance criteria which suggest compounds may be having good bioavailability as well as drug-like properties.