Structural and energetic insights into the selective inhibition of PKMYT1 against WEE1

by Selleckchem | Jan 26 2024

Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the WEE family and responsible for the regulation of CDK1 phosphorylation, has been considered a promising therapeutic target for cancer therapy. However, the highly structural conservation of the ATP-binding sites of the WEE family poses a challenge to the design of selective inhibitors for PKMYT1. Here, molecular docking, multiple microsecond-length molecular dynamics (MD) simulations and end-point free energy calculations were performed to uncover the molecular mechanism of the binding selectivity of RP-6306 toward PKMYT1 over its highly homologous kinase WEE1. The binding specificity of RP-6306 reported in previous experimental bioassays was clarified by MD simulations and binding free energy calculations. Further, the binding free energy prediction indicated that the binding selectivity of RP-6306 largely derived from the difference in the protein-ligand electrostatic interactions. The per-residue free energy decomposition suggested that the non-conserved gatekeeper residue in the hinge domain of PKMYT1/WEE1, Thr187/Asn376, is the critical factor responsible for the binding selectivity of RP-6306 toward PKMYT1. In addition, a water-mediated hydrogen bond was formed between RP-6306 and Gly191 at the hinge domain in the PKMYT1/RP-6306 complex, which was absent in the WEE1/RP-6306 complex. This study is expected to offer useful information for the design of more potent and selective PKMYT1 inhibitors.Communicated by Ramaswamy H. Sarma.

Comments:

This research seems quite intricate and detailed, focusing on understanding the binding selectivity of RP-6306 towards PKMYT1 over its closely related kinase, WEE1, which could be crucial in developing more effective and selective inhibitors for PKMYT1 in cancer therapy. The study's approach, utilizing molecular docking, MD simulations, and free energy calculations, is comprehensive and common in computational drug discovery.

The identification of the specific interactions between RP-6306 and PKMYT1/WEE1 through MD simulations and the calculation of binding free energies provides valuable insights into the molecular mechanisms underlying the selectivity of the inhibitor. The emphasis on electrostatic interactions and the role of specific residues, especially the non-conserved gatekeeper residue (Thr187/Asn376), highlights the importance of these factors in dictating binding selectivity.

Moreover, the discovery of a water-mediated hydrogen bond with Gly191 in the PKMYT1/RP-6306 complex, absent in the WEE1/RP-6306 complex, underscores potential structural differences that contribute to the selectivity of the inhibitor.

This research's implications are promising as they could guide the design of more potent and specific PKMYT1 inhibitors, potentially advancing cancer therapy strategies. The insights gained here might inform future drug development efforts targeting PKMYT1, considering the structural nuances and interactions highlighted in this study.

The contribution of Ramaswamy H. Sarma, as the communicator of this research, signifies their involvement in disseminating this critical information to the scientific community, enhancing our understanding of kinase inhibitors' selectivity and potential applications in cancer treatment.