Key result
Virtual screening identifies 5 marine-derived small molecules showing high binding affinity for TNNT2.
Why the study?
Pathogenic TNNT2 variants disrupt cardiac troponin T function leading to cardiomyopathy-associated molecular and clinical abnormalities, necessitating novel therapeutic approaches.
Computational screening identified five marine natural product ligands with high binding affinity to TNNT2 and favorable pharmacokinetic profiles as potential leads for cardiomyopathy treatment.
These computational hits require wet-lab validation; leaves open therapeutic potential in TNNT2 cardiomyopathy.
Heritable cardiomyopathies have been strongly linked to pathogenic variants in the TNNT2 gene [1], which encodes cardiac troponin T – a critical regulatory subunit of the troponin complex within the sarcomere. These mutations compromise the normal calcium-dependent regulatory mechanism of cardiac contraction by destabilizing the structural and functional integrity of the troponin-tropomyosin complex. Depending on their specific location and biochemical nature, TNNT2 mutations [2] may lead to altered calcium sensitivity, impaired contractile signaling, or sarcomeric disorganization. Such molecular perturbations are associated with divergent clinical outcomes, including hyper contractile phenotypes typical of hypertrophic cardiomyopathy [3] and hypo contractile states characteristic of dilated cardiomyopathy [4]. These changes not only reduce cardiac efficiency but also contribute to maladaptive remodeling, promoting arrythmogenic substrates and progressive cardiac dysfunction. In this investigation, we employ advanced computational strategies-specifically molecular docking and virtual screening-to identify novel small-molecule modulators that can potentially rectify the structural and functional deficits caused by disease-associated TNNT2 mutations.
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Ravi et al. (2025) studied Cardiomyopathy. Small-molecule ligands from CMNPD library was evaluated on Binding affinity (Glide score). Virtual screening and molecular docking identified five small-molecule ligands with strong binding affinities (Glide scores up to -7.423) to TNNT2 and favorable pharmacokinetic profiles.
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