Comparative binding affinity analysis of dual CDK2/FLT3 inhibitors

Abstract

Selective inhibition of cyclin‐dependent kinase 2 (CDK2) using small molecules is gaining popularity for the treatment of certain types of acute myeloid leukemia (AML). In this study, we used different molecular modeling techniques to investigate the structure–activity relationship (SAR) and binding modalities of dual CDK2/FLT3 inhibitors. The key chemical characteristics of the 3H‐pyrazolo[4,3‐f]quinoline derivatives were highlighted as descriptive colored contours using comparative molecular similarity analysis (CoMSIA). Modifying chemical groups in existing compounds along these contours could improve CDK2 selectivity over FMS‐like tyrosine kinase 3 (FLT3). We determined the ligand affinities for CDK2 by estimating the binding free energy using molecular mechanics generalized Born surface area (MM‐GBSA) and umbrella sampling (US) simulations. Reasonable correlations were found between the computed and experimental binding energies, suggesting that MM‐GBSA and US can be used to reliably predict the binding affinities of new compounds in the more potent CDK2 drug development process.

A theoretical study for the linear free energy relationship of CH bond activation and the role of the axial ligand in cytochrome P450 model complexes

“…In Structure-Activity Relationships (SAR), the electronic structure of reactants or products can be modified by variations in their substituents, and this can affect the energetics of the reaction. 45,46 The slope of a LFER is a measure of the sensitivity of the TS energy to changes in the electronic structure of the reactants or products. The steeper the slope, the more sensitive the TS energy is to changes in the reactants or products, indicating a stronger dependence of the TS on the electronic structure of the reactants or products.…”

“…In Structure–Activity Relationships (SAR), the electronic structure of reactants or products can be modified by variations in their substituents, and this can affect the energetics of the reaction 45,46 . The slope of a LFER is a measure of the sensitivity of the TS energy to changes in the electronic structure of the reactants or products.…”

Discovery of dual inhibitors of pan‐RAF and VEGFR2

“…In this context discussed above, we designed dual inhibitors of pan‐RAF and VEGFR2 for the treatment of colorectal cancer 10 . Herein, we describe the synthesis of N ‐(phenyl)‐3‐(9 H ‐purin‐6‐yl)pyridine‐2‐amine derivatives and their activities as dual inhibitors of pan‐RAF and VEGFR2 11,12 …”

“…10 Herein, we describe the synthesis of N-(phenyl)-3-(9H-purin-6-yl)pyridine-2-amine derivatives and their activities as dual inhibitors of pan-RAF and VEGFR2. 11,12 Our previously reported pan-RAF inhibitors were used as a model substrate for further modification of chemical structure to develop more potent dual inhibitors (Figure 1a). 13 We first modified the sulfonamide linker in our previous pan-RAF inhibitors 1 to amide linker in order to increase in vivo antitumor activity (Figure 1b).…”

Recent Advances in Synthetic Routes to Azacycles

“…Heterocyclic compounds are frequently identified and play an important role in human life due to their special structures. For example, heterocyclic structures are related to many biological processes and form the basic skeleton of many drug molecules and natural products [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. N -heterocycles, which contain nitrogen atoms, have attracted much attention from scientists because of their unique properties and diverse utilization.…”