<strong>Figure 1</strong><br/>
                                                    <p>\(<b>A</b>\) Schematic representation of active ROS1 kinase domain with crizotinib \(PDB: ID 3ZBF\). Mutation hotspots, indicated in red \(L2026\) and blue \(G2032\), are depicted as spheres. \(<b>B</b>\) The zoomed-in region shows the hydrophobic cluster involving residues L2000, F2004, F2103, A2106, and F2075.</p>
                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g002.png?1705989466 "
                        <strong>Figure 2</strong><br/>
                                                    <p>\(<b>A</b>\) Overlap of crizotinib extracted from complexes with c-Met \(yellow\), ALK \(magenta\), and ROS1 \(orange\). Two-dimensional representation of first-generation inhibitors, \(<b>B</b>\) crizotinib and \(<b>C</b>\) lorlatinib, with the following color scheme for the atoms: carbon \(grey\), oxygen \(red\), nitrogen \(blue\), chlorine \(green\), and fluorine \(cyan\). The interactions were analyzed and plotted using Discovery Studio Visualizer and Pymol.</p>
                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g003.png?1705989467 "
                        <strong>Figure 3</strong><br/>
                                                    <p>Two-dimensional representations of inhibitor prototypes, \(<b>A</b>\) compound 1 \(PDB: ID 7Z5X\) and \(<b>B</b>\) compound 2 \(PDB: ID 7Z5W\), with the following color scheme for the atoms: carbon \(grey\), oxygen \(red\), nitrogen \(blue\), sulfur \(yellow\), and fluorine \(cyan\). Interactions were analyzed and plotted using Discovery Studio Visualizer.</p>
                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g004.png?1705989469 "
                        <strong>Figure 4</strong><br/>
                                                    <p>Interaction map for \(<b>A</b>\) entrectinib in the ROS1 active conformation proposed by Menichincheri et al. \[<a href="#B24-crystals-14-00106" class="html-bibr">24</a>\], and \(<b>B</b>\) cabozantinib and \(<b>C</b>\) foretinib in the inactive conformation proposed by Davare et al. \[<a href="#B4-crystals-14-00106" class="html-bibr">4</a>\].</p>
                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g005.png?1705989471 "
                        <strong>Figure 5</strong><br/>
                                                    <p>\(<b>A</b>\) Superposition of the active \(green\) experimentally determined \(PDB: ID 3ZBF\) and the inactive model \(purple\) obtained through homology modeling \(template PDB: ID 4FNY\). \(<b>B</b>\) The residue F2103 side chain from the DFG motif is represented as a stick in the active structure \(green\) and the inactive model \(purple\).</p>
                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g006.png?1705989472 "
                        <strong>Figure 6</strong><br/>
                                                    <p>Representation of point mutations in the ROS1 kinase domain: \(<b>A</b>\) L2026M, \(<b>B</b>\) G2032R, and \(<b>C</b>\) D2033N. In all figures, the native ROS1 is represented in green with the mutated residues represented in yellow, while being superimposed with the native counter partner residue. Key structural motifs such as the G-loop and the <math display="inline"><semantics>
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