Molecular simulation reveals spontaneous allosteric binding of BMS-357075 to human cyclin-dependent kinase 20

Cyclin-dependent kinase 20 (CDK20) is a promising oncology target, but the lack of high-resolution complex structures limits drug development. Here, we investigated the spontaneous association of BMS-357075 with CDK20 using microsecond-scale unbiased molecular dynamics simulations, including an extended 2.0-μs trajectory to assess structural stability. The simulations suggested that BMS-357075 associated with a previously uncharacterized lateral groove on the CDK20 surface (the P_4 pocket), functioning as a potential allosteric or secondary binding site. Based on our computational model, binding was driven primarily by van der Waals interactions and proceeded through a stepwise stabilization process. Mechanistic analysis proposed a dynamic dual-anchor relay, in which BMS-357075 first engaged the shallow pocket region through polar contacts with Arg150 and then slid inward to form a stable deep-binding pose supported by a hydrogen-bond network involving Arg50 and Arg126 and extensive hydrophobic contacts. This association was accompanied by local conformational adaptation and cavity expansion, leading to high predicted druggability. Furthermore, dynamic network analysis indicated structural coupling between this lateral groove and the catalytic core (Asp127), providing a plausible mechanism for structural perturbation. Sequence and structural mapping revealed that while the ligand interacts with conserved residues, the P_4 pocket is flanked by a structural loop unique to CDK20. Overall, this study characterizes a multi-step association pathway of BMS-357075 and identifies a structurally stable surface cavity. These findings highlight a putative cryptic site that offers a promising structural template for designing highly selective CDK20 inhibitors.