Jan 2026· Journal of Chemical Information and Modeling· Vol 66, pp. 1865-1879· 0 citations· 67 references
Computer ScienceMedicine
TL;DR
This study leverages an integrated computational strategy combining molecular dynamics simulation, end-point binding free-energy calculation, and enhanced sampling technologies to elucidate the dynamic characteristics of RAS-ligand-CYPA interactions and uncover the dynamic process of stabilizer-mediated KRAS-CYPA stabilization.
Abstract
Molecular glues, including protein degraders and protein-protein interaction (PPI) stabilizers, have emerged as a new paradigm of drug design for regulating interactions between biomacromolecules; yet it is still a challenge for rational design of molecular glues. KRAS, as a prevalent oncogenic driver, is notoriously difficult to target by traditional small molecular drugs due to its challenging binding surface and frequent mutations. Although the small molecular drug RMC7977 has been designed as a PPI stabilizer for stabilizing the inherently weak RAS-CYPA interaction, the precise molecular mechanism underlying its stabilization effect and selectivity difference requires a deeper understanding. To this end, we leverage an integrated computational strategy combining molecular dynamics (MD) simulation, end-point binding free-energy calculation, and enhanced sampling technologies to elucidate the dynamic characteristics of RAS-ligand-CYPA interactions. Our result exhibits a high correlation between the predicted binding affinities and the experimental observations, demonstrating that RMC7977, acting as a strong PPI stabilizer, significantly enhances the stability of the KRAS-CYPA interaction, where, by delicately remodeling the protein-protein interface, the drug optimizes various interactions. Moreover, the results also uncover the dynamic process of stabilizer-mediated KRAS-CYPA stabilization and the mechanistic origin of the binding selectivity. This study provides essential molecular-level insights into RMC7977's function and offers a valuable computational framework for evaluating the stabilization effect of ligands targeting the KRAS-CYPA and other challenging PPI systems.
Background: The HSP90 and CDC37 molecular chaperone complex governs the
stability and function of numerous client protein kinases, making it a crucial cancer target. Given their central role, disrupting this interaction induces proteotoxic stress and inhibits tumor progression. Therapeutic peptides are the mainstay of treatment for disruption of key interactions, yet they face limitations such as toxicity, resistance, and poor stability. Aim: This study aims to leverage peptidomimetics as novel disruptors of the HSP90–CDC37 interaction. Methods: Two peptides, a 9-mer and a 7-mer, were rationally designed by analyzing key regions facilitating HSP90–CDC37 complex formation. In silico mutational analysis identified crucial residues essential for interaction and ultimately supported the retrieval of peptidomimetic compounds. Molecular docking and binding free energy analysis were employed to explore the affinity of the mimetics for HSP90. The ADMET screening ensured drug-like properties of the compounds. Results: Among the tested compounds, MMs02350546 emerged as the most promising, maintaining strong interactions with the critical Glu47 residue, disrupting ATPase activity, and destabilizing oncogenic proteins. Molecular dynamics simulations provided insight into the atomic-level fluctuations upon ligand binding and confirmed the favorable positioning of the molecule in the binding pocket of HSP90. Conclusion: Collectively, the findings highlight MMs02350546 as a potential disruptor of HSP90–CDC37 interaction, presenting a promising therapeutic strategy against cancer via chaperone complex destabilization. The molecular feature, particularly the presence of the triazole moiety in the mimetic, is hypothesized to play a pivotal role in the compound’s bioactivity. This study may further pave the way toward preclinical evaluation of peptidomimetics as a novel modulator of oncogenic protein stability.
Whether binding specificity and partner selection in protein-protein interactions (PPIs) can be reliably inferred from static structures or require more dynamic, pathway-resolved energetic analyses remains an open question. To explore this, we focus on the ornithine decarboxylase (ODC)-antizyme isoform 1 (Az1)-antizyme inhibitor (AzIN) system, a well-characterized competitive PPI network that plays a critical role in regulating polyamine homeostasis. By combining extensive all-atom molecular dynamics simulations with biochemical experiments and the development of a new tool, we uncover key dynamic features of the static and recognition pathway interaction. Based on these, we designed novel antizyme isoforms (NAZs). Our analysis, using residue-resolved energetic landscapes, reveals critical determinants of binding specificity and partner selection that static structures alone cannot capture. These insights guide the engineering of NAZs that either directly engage ODC or modulate Az1 availability. This work provides a new perspective, demonstrating that dynamic energetic landscapes, rather than static structures, are key to understanding and modulating competitive protein recognition. Additionally, our DyResEL tool enables broader, more detailed analyses of energetic contributions, offering a versatile approach for exploring PPIs in various biological contexts.
Baolin Guo, Qian Xue, Fan Yang et al.· Journal of Chemical Informat...· 0 citations
Background: Paclitaxel is a cornerstone chemotherapeutic agent widely used in breast cancer treatment, primarily through the stabilization of microtubule dynamics. Beyond its canonical tubulin-targeting activity, increasing evidence suggests that paclitaxel may engage additional molecular targets, contributing to its complex pharmacological profile. In this study, an integrated computational workflow was applied to evaluate the structural compatibility between paclitaxel and the neurokinin-2 receptor (NK2R), a G protein-coupled receptor involved in tumor-associated inflammatory and proliferative signaling pathways. Physicochemical profiling and target prediction were performed using SwissADME and SwissTargetPrediction, followed by molecular docking and molecular dynamics simulations using AutoDock Vina and GROMACS 2024.1. Paclitaxel exhibited physicochemical properties consistent with transient interactions in hydrophobic transmembrane environments. Docking analysis identified a plausible binding mode within the NK2R transmembrane cavity, primarily stabilized by hydrophobic contacts. Molecular dynamics simulations over 100 ns revealed stable ligand occupancy and overall complex stability, while MM-PBSA calculations indicated a favorable transient association. The predicted interaction is consistent with secondary or non-canonical receptor engagement. While NK2R is not established as a pharmacological target of paclitaxel, the results support the structural feasibility of a previously uncharacterized receptor interaction and provide a reproducible computational framework for exploring GPCR-associated effects of cytotoxic agents.
C. Duda-Seiman, L. Tarțău, Bogdan Hoinoiu et al.· Bioengineering· 0 citations
This work highlights how distinct inhibitors exploit different conformational states of cKIT and demonstrates the value of integrating structural analyses, biophysical measurements, calculations and molecular simulations to define the mechanism of kinase inhibition.
Irene Cipollone, Carmen Gratteri, C. Talarico et al.· International Journal of Bio...· 0 citations
Kirsten rat sarcoma virus protein (KRAS) is one of the most important targets in current drug discovery. Its intrinsic properties, including a high structural flexibility and a shallow polar pocket, make KRAS extremely difficult to target. In fact, for a long time it was considered undruggable. A better understanding of its structure and dynamics will help to advance drug discovery efforts. KRAS is a GTPase, which is highly relevant for the growth, proliferation, and differentiation of cells. Several oncogenic mutations have been identified, suggesting that KRAS could be an excellent target in the fight against cancer. In this work, we use molecular dynamics simulations to highlight the challenges of this protein in computational drug design. We start from a characterization of the structural flexibility and the diversity in observed molecular interactions. Then we quantify the thermodynamic reasons for the increased stability of the G12C mutant in the active, GTP-bound state. For this we use two thermodynamic cycles and find that the alchemical mutation leads to internally consistent results, in agreement with the biological observations. Furthermore, we explore the use of Accelerated Enveloping Distribution Sampling (A-EDS) to efficiently screen a small set of fragments with the strongest binding affinity. The screening mode of A-EDS already allows for the identification of the most favorable candidate molecules. Subsequently, further optimization of the A-EDS parameters facilitates a quantification of the relative binding affinities in terms of free energies.
Nadine Grundschober, Viktorija Dujmovic, C. Oostenbrink et al.· Journal of Chemical Informat...· 0 citations
Macrocyclic peptides are attracting attention as a promising therapeutic modality for addressing intracellular targets that are traditionally difficult to address with conventional small molecules or antibodies. In this study, we present the chemical optimization process behind the development of AUBE00 (AP7400, compound 30), a KRAS-selective inhibitor based on a scaffold similar to LUNA18, an orally bioavailable macrocyclic peptide RAS inhibitor. Achieving KRAS isoform selectivity is exceptionally challenging due to the nearly identical backbone structures of KRAS, HRAS, and NRAS (Cα RMSD < 1.1 Å). The success of this study relied on two critical factors: (1) achieving conformational control of the flexible N-alkyl group through a bridging structure linked to the adjacent side chain, which enabled the exploitation of subtle interaction energy differences among the isoforms; and (2) overcoming the trade-off between improved KRAS selectivity and reduced permeability associated with P-glycoprotein (P-gp) substrate liability by employing a modified Caco-2 membrane permeability assay to recover oral bioavailability. Our results demonstrate that a conformational rigidification through a bridged scaffold, implemented while preserving membrane permeability, is a highly effective strategy for achieving isoform selectivity. This study establishes a generalizable design principle for orally bioavailable macrocyclic peptides targeting intracellular proteins that require mutation or isoform selectivity.
M. Kage, Hatsuo Kawada, Koji Takano et al.· Journal of the American Chem...· 0 citations
The new ChartNet training dataset could improve the accuracy of vision-language models that help analyze business trends or interpret scientific figures.
