Applying Ligands Profiling Using Multiple Extended Electron Distribution Based Field Templates and Feature Trees Similarity Searching in the Discovery of New Generation of Urea-Based Antineoplastic Kinase Inhibitors

Abstract

This study provides a comprehensive computational procedure for the discovery of novel urea-based antineoplastic kinase inhibitors while focusing on diversification of both chemotype and selectivity pattern. It presents a systematic structural analysis of the different binding motifs of urea-based kinase inhibitors and the corresponding configurations of the kinase enzymes. The computational model depends on simultaneous application of two protocols. The first protocol applies multiple consecutive validated virtual screening filters including SMARTS, support vector-machine model (ROC = 0.98), Bayesian model (ROC = 0.86) and structure-based pharmacophore filters based on urea-based kinase inhibitors complexes retrieved from literature. This is followed by hits profiling against different extended electron distribution (XED) based field templates representing different kinase targets. The second protocol enables cancericidal activity verification by using the algorithm of feature trees (Ftrees) similarity searching against NCI database. Being a proof-of-concept study, this combined procedure was experimentally validated by its utilization in developing a novel series of urea-based derivatives of strong anticancer activity. This new series is based on 3-benzylbenzo[d]thiazol-2(3H)-one scaffold which has interesting chemical feasibility and wide diversification capability. Antineoplastic activity of this series was assayed in vitro against NCI 60 tumor-cell lines showing very strong inhibition of GI50 as low as 0.9 uM. Additionally, its mechanism was unleashed using KINEX™ protein kinase microarray-based small molecule inhibitor profiling platform and cell cycle analysis showing a peculiar selectivity pattern against Zap70, c-src, Mink1, csk and MeKK2 kinases. Interestingly, it showed activity on syk kinase confirming the recent studies finding of the high activity of diphenyl urea containing compounds against this kinase. Allover, the new series, which is based on a new kinase scaffold with interesting chemical diversification capabilities, showed that it exhibits its “emergent” properties by perturbing multiple unexplored kinase pathways.

3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

“…The accuracy in the alignment of molecules and determination of bioactive conformations are the important factors to be considered while building a 3D‐QSAR model. Before 3D‐QSAR model development, template generation was carried out using “FieldTemplater.” [ 30 ] The XED force field [ 31 ] was used to obtain molecular field points (negative and positive electrostatic, van der Waals, and hydrophobic) of reference compounds 1–3 . Herein, the reference ligands were considered which represents the studied data set and are reported with lowest IC 50 value against the target “ALDH1A1.” For template generation, maximum numbers of conformations were set as 500, while the other parameters included the number of high‐T dynamics runs for flexible rings, gradient cutoff for conformer minimization, filter duplicate conformers at RMS, and energy window values were used with default settings.…”

“…Before 3D-QSAR model development, template generation was carried out using "FieldTemplater." [30] The XED force field [31] was used to obtain molecular field points (negative and positive electrostatic, van der Waals, and hydrophobic) of reference compounds 1-3. Herein, the reference ligands were considered which represents the studied data set and are reported with lowest IC 50 value against the target "ALDH1A1.…”

Synthesis and in vitro antiproliferative activity of novel pyrazolo[3,4-d]pyrimidine derivatives

“…The pyrazoles were cyclized to pyrazoloij3,4-d]pyrimidine by refluxing in formamide, 21,22 then the 4-chloro derivatives were prepared by chlorination with phosphorus oxychloride. 23 In Scheme 1, the 4-amino diphenyl urea derivatives 2b-e were synthesized in 2 steps first by reacting 4-nitroaniline with the appropriate aryl isocyanate in methylene chloride, 24 then reduction of the produced 4-nitro derivative using stannous chloride dihydrate. 25 The target products 3a-e were prepared in moderate to high yields from the reaction of the chloro derivatives 1a and b with the appropriate amines 2b-e.…”