Three Dimensional Quantitative Structure-Activity Relationship of 5H-Pyrido[4,3-b]indol-4-carboxamide JAK2 Inhibitors

Abstract

Janus kinase 2 (JAK2) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family of kinases, which play an important role in survival, proliferation, and differentiation of a variety of cells. JAK2 inhibitors are potential drugs for the treatment of myeloproliferative neoplasms. The three dimensional quantitative structure-activity relationships have been studied on a series of JAK2 inhibitors by comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The CoMFA model had a cross-validated coefficient q2 of 0.633, and the relation non-cross-validated coefficient r2 of 0.976. The F value is 225.030. The contributions of steric and electrostatic fields to the activity are 55.2% and 44.8%, respectively. For the CoMSIA study, the q2, r2, and F values of the model are 0.614, 0.929, and 88.771, respectively. The contributions of steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond donor fields to the activity are 27.3%, 23.9%, 16.4%, 21.7%, and 10.7%, respectively. The CoMFA and CoMSIA models showed strong predictive ability, and the 3D contour plots give the basis on the structure modification of JAK2 inhibitors.

Construction of Quantitative Structure Activity Relationship (QSAR) Models to Predict Potency of Structurally Diversed Janus Kinase 2 Inhibitors

“…Several QSAR models on JAK2 were performed. The training set of 22, 31, 40, 42, 51 and 161 leads to the R2 of 0.97 [28], 0.97 [23], 0.929 [27], 0.970 [26], 0.93 [25] and 0.869 [24], respectively. It can be seen that QSAR models built from lower training sets tend to have better performance.…”

“…Several QSAR models were developed in the hope to drive the novel compounds with better properties against kinase [15,16,17,18,19,20,21,22]. To understand the origin and bioactivities of JAK inhibitors, models were developed with the hope to identify important pharmacophores and substructures using pharmacophores and 3D QSAR [23,24,25,26,27,28,29,30,31,32,33,34,35]. Due to the polypharmacological nature of compounds, multi-target QSAR models have been also developed to handle the interaction of multiple targets of JAK inhibitors.…”

3D-QSAR, molecular docking and molecular dynamics analysis of pyrazole derivatives as MALT1 inhibitors

“…The original model was considered acceptable if the new model yielded q 2 and r 2 much lower than those of the original model. 25…”

“…The original model was considered acceptable if the new model yielded q 2 and r 2 much lower than those of the original model. 25 2.4.2 External verification. A strictly reliable 3D-QSAR model requires both internal and external validation.…”