Cheminfomatic-based Drug Discovery of Human Tyrosine Kinase Inhibitors

Abstract

Receptor Tyrosine Kinases (RTKs) are essential components for regulating cell-cell signaling and communication events in cell growth, proliferation, differentiation, survival and metabolism. Deregulation of RTKs and their associated signaling pathways can lead to a wide variety of human diseases such as immunodeficiency, diabetes, arterosclerosis, psoriasis and cancer. Thus RTKs have become one of the most important drug targets families in recent decade. Pharmaceutical companies have dedicated their research efforts towards the discovery of small-molecule inhibitors of RTKs, many of which had been approved by the U.S. Food and Drug Administration (US FDA) or are currently in clinical trials. The great successes in the development of small-molecule inhibitors of RTKs are largely attributed to the use of modern cheminformatic approaches to identifying lead scaffolds. Those include the quantitative structure-activity relationship (QSAR) modeling, as well as the structure-, and ligand-based pharmacophore modeling techniques in this case. Herein we inspected the literature thoroughly in an effort to conduct a comparative analysis of major findings regarding the essential structure-activity relationships (SARs)/pharmacophore features of known active RTK inhibitors, most of which were collected from cheminformatic modeling approaches.

Computational Characterization of Membrane Proteins as Anticancer Targets: Current Challenges and Opportunities

“…The structural analysis of the kinase domain, on the other hand, has been very useful to identify and prioritize small molecules targeting this domain, and to explain the reasons for resistance [62]. The wealth of experimental data for kinase inhibitors has made it possible to use ML models to screen not only potency for wildtype [63] and mutant RTKs [64], but also clinical responses associated with gene expression signatures [65]. Beyond small molecule screening, ML models have also been employed to generate de novo RTK inhibitors by combining 2D and 3D features of known kinase inhibitors [66].…”

Optimization Of Cancer Treatment Through Overcoming Drug Resistance

“…Combined chemotherapy and immunotherapy: It is promising that immunotherapy may reform the treatment of cancer by inducing, augmenting or suppressing immune responses against cancer cells, which also include monoclonal antibodies, cancer vaccines, and inhibitors of immune checkpoints such as anti PD-1/PDL-1 [ 131 , 132 ].…”

Quantitative analysis of "structure - anticancer activity" and rational molecular design of bi-functional VEGFR-2/HDAC-inhibitors

“…Хотя именно эти показатели характеризуют качество и прогнозирующую способность модели и ее возможность использования в дальнейших исследованиях. К сожалению, большинству существующих QSAR-моделей ингибиторов VEGFR-1, 2 [Yu et al, 2007;Sun et al, 2013;Rajagopalan et al, 2013;Reid et al, 2016;Patel et al, 2009] присущи вышеуказанные проблемы и ограничения. Следует отметить, что авторами публикации [Marzaro et al, 2011] в рамках вышеуказанной перспективной стратегии разработки многофункциональных противоопухолевых средств предложены мультитаргетные классификационные QSAR-модели, количественно описывающие связь «структура -антитирозинкиназная активность», в том числе в отношении VEGFR-1.…”