Ascertaining a Structural Basis in Drug Discovery and Development

Abstract

Published as part of Journal of Medicinal Chemistry special issue “Structural Biology in Drug Discovery and Development”. Figure 1. Intermolecular interactions that enable unique targeting of the EGFR kinase domain by small-molecule tyrosine kinase inhibitors. A) Lazertinib in complex with T790M-containing EGFR shows van der Waals interactions consistent with the selectivity against this T790M-dependent drug resistance (PDB ID 7UKW). Adapted from reference (6) with permission. Copyright 2022 American Chemical Society. B) Trisubstituted imidazole LN2084 in complex with EGFR showing H-bonding to the conserved catalytic lysine K745 (PDB ID 6V5N). Adapted from reference (5) with permission. Copyright 2020 American Chemical Society. Figure 2. Alternative interactions between the EGFR kinase protein and bivalent kinase inhibitors. X-ray cocrystal structures and corresponding interaction frequencies with based on MD simulations of compound 1 (A and B, PDB ID 8FV3) and 2 (C and D, PDB ID 8FV4), respectively. For B and D: only interactions occurring in more than 20% of the simulation time are shown and detailed information can be found in reference (9). Note the analogous hydrogen bonding interactions between the ligand and the hinge-region M793 while K745 forms direct hydrogen bonds with the ligand in the cocrystal structures that are observed to be water-mediated hydrogen bonds in the MD simulations. Reproduced from reference (9). Available under a CC-BY 4.0 license. Copyright 2024 Wittlinger, F.; Ogboo, B. C.; et al. The ideas and scope of this editorial have benefitted from helpful comments from Andrew Gulick, Department of Structural Biology, The State University of New York at Buffalo. Additional input from Blessing Ogboo, Tahereh Damghani, and Kishan Patel is also appreciated. D.E.H. acknowledges generous support from the National Institute of General Medical Sciences of the NIH (R35GM155353-01), National Center for Advancing Translational Sciences of the NIH under award number UL1TR001412-08 (BTC K Scholar Award), and startup funds from The State University of New York. This article references 34 other publications. This article has not yet been cited by other publications.