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Covalent Binding of BMP-2 on Surfaces Using a Self-assembled Monolayer Approach

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Shaping Antimalarials: A Geometry-First Approach to PfCLK3 Covalent Inhibitors.

Skye B Brettell¹, Carla Fuentes-Guerra Bustos¹, Saumya Sharma²

¹School of Chemistry, The Advanced Research Centre, University of Glasgow, 11 Chapel Lane, Glasgow G11 6EW, U.K.

Journal of Medicinal Chemistry

|January 31, 2026

Summary

This summary is machine-generated.

Developing new antimalarial drugs is crucial due to rising Plasmodium falciparum resistance. This study optimized covalent kinase inhibitors by focusing on geometry, leading to a potent new compound with improved stability.

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Area of Science:

Medicinal Chemistry
Parasitology
Drug Discovery

Background:

Antimalarial drug resistance in Plasmodium falciparum necessitates novel therapeutic strategies.
Plasmodium falciparum Clk3 (PfCLK3) is a validated target for antimalarial drug development.
Covalent kinase inhibitors (CKIs) offer durable inhibition but often prioritize warhead reactivity over optimal geometry.

Purpose of the Study:

To develop optimized covalent inhibitors of PfCLK3 using a geometry-first approach.
To investigate the impact of warhead and linker geometry on covalent bond formation with PfCLK3.
To identify novel CKI drug candidates with potent antimalarial activity and favorable drug-like properties.

Main Methods:

Systematic structural modification of a chloroacetamide-based covalent inhibitor scaffold.
Evaluation of covalent engagement with PfCLK3 Cys368 residue.
Assessment of antiparasitic activity and metabolic stability of optimized compounds.

Main Results:

A geometry-first approach successfully optimized covalent PfCLK3 inhibitors.
Maintaining the α-reactive geometry allowed covalent engagement with less reactive electrophiles.
The methyl sulfamate analogue SB5-171 demonstrated potent antimalarial activity (EC50 = 104 nM) and enhanced metabolic stability (t1/2 = 35 min).

Conclusions:

Geometric optimization is a viable strategy for designing selective and effective covalent kinase inhibitors.
This approach decouples covalent engagement from high intrinsic reactivity, leading to improved drug-like properties.
The developed compounds provide a rational framework for future antimalarial CKI drug discovery.