Al Mokhtar Lamsabhi

Oxygenated 9H-carbazole-3-carbaldehyde scaffolds as cerebral cavernous malformation-relevant protein–protein interaction disruptors of the HEG1–KRIT1 interface

Breaking the Myb–KIX Alliance: Structure‐Guided Discovery of Biaryl Hydroxy‐Naphthamides as Disruptors of the c‐Myb–CBP/p300 KIX Protein–Protein Interaction

3‐hydroxy‐2‐naphthamides are established as promising scaffolds for targeting the c‐Myb–CBP/p300 KIX interface and are supported as the most conformationally stable interfacial binders.

Targeting the c-Myb-CBP/p300 KIX protein-protein interaction with quinone-methide triterpenes: In silico mechanistic insights and MST biochemical validation.

Tingenone is identified as a promising scaffold for the development of new c-Myb-CBP/p300 KIX PPI inhibitors, having produced the clearest signatures of interfacial weakening and the most favorable disruption metrics.

Structure-Guided Identification of 2-Arylbenzothiazole as disruptors for the Oncogenic MTDH-SND1 Protein-Protein Interaction.

2-arylbenzothiazoles are established as a promising chemotype for MTDH-SND1 PPI inhibition and provide a validated computational-to-experimental framework for discovering and optimizing MTDH-directed therapeutics.

Structure‐Based Discovery of Fumiquinazolines as Skp2–Cks1 Protein–Protein Interaction Disruptors: Mechanistic Computational Insights and Experimental Validation

Findings identify Fumiquinazoline D as an early‐stage biochemical hit for disruption of the Skp2–Cks1 interaction and as a potential scaffold for further mechanistic validation and medicinal‐chemistry investigation.

Structure-guided delineation of umbelliferyl phosphate-based disruptors of the c-Myb-CBP/p300 KIX protein-protein interaction.

The interaction between c-Myb and the CBP/p300 KIX domain is a critical transcriptional regulatory event and an attractive target for the development of candidate disruptors of the recombinant c-Myb-KIX interaction. In this study, we used an integrated computational and experimental strategy to identify new small molecules capable of disrupting this protein-protein interaction. A focused Umbelliferyl phosphate scaffold library was subjected to stepwise virtual screening via drug-likeness assessment and docking to the c-Myb-binding region of the KIX domain and short molecular dynamics refinement. Selected compounds were then evaluated by 500 ns molecular dynamics simulations, MM/PBSA analysis, free energy landscape (FEL) mapping, and finally by microscale thermophoresis (MST) assay. Computational analyses showed that stable ligand binding did not necessarily translate into disruption of the c-Myb-KIX interface, allowing separation of compounds that stabilized the complex from those predicted to weaken it. Consistent with this distinction, ΔΔGPPIanalysis identified only MUP and Naphthol AS-BI phosphate as protein-protein interaction-weakening ligands, with Naphthol AS-BI phosphate showing the strongest predicted disruptive effect (ΔΔGPPI=+3.25 kcal/mol), whereas DiFMUP and Naphthol AS-D phosphate were predicted to stabilize the complex. Among the tested molecules, Naphthol AS-BI phosphate showed the clearest disruption-like behavior in silico and was the most potent inhibitor in vitro, with an IC₅₀ of 18.9 ± 0.6 μM. Importantly, MUP emerged as the most promising umbelliferyl phosphate-derived hit, displaying measurable inhibitory activity (IC₅₀ = 33.5 ± 0.3 μM) comparable to the reference Naphthol AS-E phosphate (IC₅₀ = 31.2 ± 1.3 μM) and a more favorable predicted ADMET profile. Overall, this work identifies new chemical starting points for targeting the c-Myb-CBP/p300 KIX interaction and supports MUP as an attractive scaffold for further optimization.

Structure-based discovery of diphenylpyrazines as disruptors of the Skp2–Cks1 protein–protein interaction: computational insights and biochemical validation

Findings validate the diphenylpyrazine scaffold as a promising chemotype for Skp2–Cks1 inhibition and identify C3 as a strong lead for further optimization.