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Updated: Jan 27, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Discovery of selective Mcl-1 inhibitors via structure-based design and structure-activity relationship analysis
Nianzhe He1, Peng Liu2, Ziqian Wang3
1State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.
Abstract:
Based on Nap-1, a Mcl-1/Bcl-2 dual inhibitor reported by our group, we carried out a structure-guided molecular design and structure-activity relationship (SAR) analysis to study structural features contributing to Mcl-1 binding selectivity and affinity. A series of derivatives of Nap-1 with various pharmacophores were synthesized and among them a dual Mcl-1/Bcl-2 inhibitor A4 with enhanced affinities (IC50 = 0.15 μM for Mcl-1, 0.43 μM for Bcl-2) and a selective Mcl-1 inhibitor B9 with a 20-fold selectivity over Bcl-2 (IC50 = 0.51 μM vs 9.46 μM) were obtained by enzyme linked immunosorbent assay (ELISA). The SAR data and binding modes of A4 and B9 investigated by 2D-NMR derived docking study illustrated that p2 pockets exhibiting different geometry and binding features between Mcl-1 and Bcl-2 contribute to specific binding properties of Mcl-1. In addition, apoptosis-inducing potencies of A4 and B9 were consistent with their binding selectivity determined in vitro.
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