Volume : 13, Issue : 09, September – 2026

Title:

PROTEOLYSIS TARGETING CHIMERAS (PROTACS): MECHANISTIC BASIS, COMPUTATIONAL AND ARTIFICIAL-INTELLIGENCE-DRIVEN DESIGN, PRECISION ENGINEERING, AND CLINICAL TRANSLATION

Authors :

K. Priyaranjan, Chetan Kasyap Vepachedu*

Abstract :

Targeted protein degradation (TPD) broadens the druggable proteome beyond classical occupancy-based inhibitors. Proteolysis targeting chimeras (PROTACs) are heterodimeric small-molecules that link the protein of interest (POI) and an E3 ubiquitin ligase into a ternary complex which repurposes the ubiquitin-proteasome system to degrade the target. Since a single PROTAC molecule can trigger multiple rounds of degradation, this event-driven pharmacology operates under sub-stoichiometric dosing and is capable of disabling scaffolding activity that is out of reach for inhibition. This review discusses five related themes. First, we introduce PROTAC structure and mechanism, focusing on ternary-complex cooperativity and the hook effect. Second, we present the use of computational and AI-assisted tools, such as docking (Rosetta, PRosettaC), deep learning structure prediction (AlphaFold2/3, RoseTTAFold-All-Atom), and machine learning linkers design and degradation prediction. Third, we discuss light-, radiation-, ultrasonic-, and bioorthogonal click-release responsive platforms enabling spatiotemporally controlled PROTAC delivery. Fourth, we highlight the approaches towards brain-penetrant PROTACs addressing neuro-oncology and neurodegenerative diseases. Finally, we present the clinical development status of late-stage androgen- and estrogen-receptor degraders as well as lysosomal modalities allowing TPD to go beyond intracellular targets.
Keywords: PROTACs; Targeted protein degradation; Ubiquitin-proteasome system; Computational drug design; Artificial intelligence; E3 ubiquitin ligase

Cite This Article:

Please cite this article in press Chetan kasyap vepachedu et al., Proteolysis Targeting Chimeras (Protacs): Mechanistic Basis, Computational And Artificial-Intelligence-Driven Design, Precision Engineering, And Clinical Translation.,. Indo Am. J. P. Sci, 2026; 13(10).

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