Binding selectivity-dependent molecular mechanism of inhibitors towards CDK2 and CDK6 investigated by multiple short molecular dynamics and free energy landscapes

Abstract

Understanding selectivity-dependent molecular mechanism of inhibitors towards CDK2 over CDK6 is prominent for improving drug design towards the CDK family. Multiple short molecular dynamics (MD) simulations combined with MM-GBSA approach are adopted to investigate molecular mechanism on binding selectivity of inhibitors X64, X3A, and 4 AU to CDK2 and CDK6. The RMSF analysis and calculations of molecular surface areas indicate that local structural and global flexibility of CDK6 are stronger than that of CDK2. Based on dynamics cross-correlation maps (DCCMs), motion modes of CDK2 and CDK6 produce difference due to associations of X64, X3A, and 4 AU. The calculated binding free energies (BFEs) demonstrate that the compensation between binding enthalpy and entropy of X64, X34, and 4 AU is a key force driving selectivity of inhibitors towards CDK2 over CDK6. This work provides valuable information for designing highly selective inhibitors towards CDK2 and CDK6 and further promotes identification of efficient anticancer drugs in the future.

Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation

“…However, in the last 200 ns of the simulation, hydrogen bonds were mainly formed with H100 for 80.27% occupancy ( Supplementary Figure S13 ). The formation of these two hydrogen bonds, which formed between abemaciclib and the hinge loop of CDK6, was consistent with the results of experimental and theoretical studies ( Yuan et al, 2021 ; Chen et al, 2022 ; Sokolsky et al, 2022 ; Wang et al, 2023 ). In addition, the hydrogen bond between the atom N4 of abemaciclib and the NZ atom of K43 was not unstable from the occupancy with 22.07% for the 500 ns simulation and 20.74% for the last 200 ns simulation, respectively.…”

Deciphering Selectivity Mechanism of BRD9 and TAF1(2) toward Inhibitors Based on Multiple Short Molecular Dynamics Simulations and MM-GBSA Calculations

“…In the current study, in order to illustrate the selective mechanism of BRD9 and TAF1(2), three small-molecule inhibitors, 67B, 67C, and 69G, were chosen to determine their binding selectivity for BRD9 and TAF1(2) by performing MSMD simulations and binding free energy computations. Encouragingly, MSMD simulations can extract more rational conformational sampling than cMD simulations, which has been verified in previous works [ 59 , 60 , 61 ]. Furthermore, principal component analysis (PCA) [ 62 , 63 ], dynamics cross-correlation maps (DCCMs), and free energy landscapes (FELs) were combined to investigate the conformational variations and internal dynamics of BRD9 and TAF1(2) caused by inhibitor associations.…”

Structure‐Based Approaches for the Prediction of Alzheimer's Disease Inhibitors: Comparative Interactions Analysis, Pharmacophore Modeling and Molecular Dynamics Simulations

“…For instance, a study has demonstrated that understanding the binding selectivity of inhibitors towards CDK2 as opposed to CDK6 is important for enhancing drug design. [5] Similarly, the binding specificity of inhibitors to CDK5 is also a significant area of research, particularly in the context of neuropathological disorders such as Alzheimer's disease. [6] The role of the tubulin-associated unit (tau) protein in the neurodegenerative process is still unclear.…”

“…In terms of drug design, the binding specificity of inhibitors is a crucial aspect. For instance, a study has demonstrated that understanding the binding selectivity of inhibitors towards CDK2 as opposed to CDK6 is important for enhancing drug design [5] . Similarly, the binding specificity of inhibitors to CDK5 is also a significant area of research, particularly in the context of neuropathological disorders such as Alzheimer's disease [6] …”