Computational Investigation of Indazole Scaffolds as Tyrosine Kinase Inhibitors Using Molecular Docking and ADMET Prediction

Introduction

Lung cancer is the second most commonly diagnosed cancer worldwide after breast cancer. Every year, it is said to kill a large number of people. The most common type of lung cancer is non-small cell lung cancer (NSCLC), which accounts for 85 percent of all cancer cases^{1, 2}. Angiogenesis is known to be stimulated by abnormal activation of vascular endothelial growth factor receptors (VEGFR), which causes cell proliferation, migration, survival, and permeability of blood vessels^{3, 4}. VEGFRs are divided into three subtypes: VEGFR-1, VEGFR-2, and VEGFR-3⁵. VEGFR-2 inhibitors are small molecules that suppress angiogenesis and lymphangiogenesis by binding to the ATP binding region of VEGFR-2⁶. Furthermore, in vitro and in vivo studies show that VEGF levels are elevated in tuberculosis (TB) patients ^{7, 8}. Aside from the several VEGFR-2 inhibitors that have been approved by the FDA or are in clinical development, there are other initiatives underway to discover novel ones for cancer treatment. Novel drugs having such potential are attempted. Example includes, sunitinib is an indole based antineoplastic agent who inhibits multiple receptor tyrosine kinases⁹, nintedanib is also an indole based triple angiokinase inhibitor that targets numerous receptor tyrosine kinases and non-receptor tyrosine kinases (nRTKs) ^{10, 11}, urea derivative sorafenib interacts with number of internal (cRAF, BRAF) and cell surface (KIT, FLT-3, VEGFR-2, 3 and PDGFR-β) kinases^{12, 13}, indazole based pazopanib is an second generation multi-targeted tyrosine kinase inhibitor of VEGFR-1, -2 and -3, PDGFR-α, -β and c-KIT¹⁴, and another indazole based drug axitinib is an inhibitor of VEGFR-1,-2 and -3^{15, 16}.

Indazole scaffolds have been extensively studied for the development of newer pharmaceutical drugs; in particular, numerous indazole derivatives exhibit their capacity to inhibit VEGFR-2^{17, 18}. Hence, in this context, our research focuses on the computational design of new indazole based molecules with the pharmacophore characteristics of VEGFR-2 inhibitors. These molecules are made up of various bio-isosters, each of which binds to a distinct area of the ATP binding site^{19, 20}. In this study, molecular docking analysis along with pharmacokinetic ADMET and drug likeness prediction were carried out to evaluate the newly designed indazole scaffolds as potent tyrosine kinase VEGFR-2...