ArticleJournal of bioenergetics and biomembranes2024
Fragment-based drug design of novel inhibitors targeting lipoprotein (a) kringle domain KIV-10-mediated cardiovascular disease.
Article in Journal of bioenergetics and biomembranes, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Cardiovascular diseases (CVDs) are the leading cause of death globally, attributed to a complex etiology involving metabolic, genetic, and protein-related factors. Lipoprotein(a) (Lp(a)), identified as a genetic risk factor, exhibits elevated levels linked to an increased risk of cardiovascular diseases. The lipoprotein(a) kringle domains have recently been identified as a potential target for the treatment of CVDs, in this study we utilized a fragment-based drug design approach to design a novel, potent, and safe inhibitor for lipoprotein(a) kringle domain. With the use of fragment library (61,600 fragments) screening, combined with analyses such as MM/GBSA, molecular dynamics simulation (MD), and principal component analysis, we successfully identified molecules effective against the kringle domains of Lipoprotein(a). The hybridization process (Breed) of the best fragments generated a novel 249 hybrid molecules, among them 77 exhibiting superior binding affinity (≤ -7 kcal/mol) compared to control AZ-02 (-6.9 kcal/mol), Importantly, the top ten molecules displayed high similarity to the control AZ-02. Among the top ten molecules, BR1 exhibited the best docking energy (-11.85 kcal/mol ), and higher stability within the protein LBS site, demonstrating the capability to counteract the pathophysiological effects of lipoprotein(a) [Lp(a)]. Additionally, principal component analysis (PCA) highlighted a similar trend of motion during the binding of BR1 and the control compound (AZ-02), limiting protein mobility and reducing conformational space. Moreover, ADMET analysis indicated favorable drug-like properties, with BR1 showing minimal violations of Lipinski's rules. Overall, the identified compounds hold promise as potential therapeutics, addressing a critical need in cardiovascular medicine. Further preclinical and clinical evaluations are needed to validate their efficacy and safety, potentially ushering in a new era of targeted therapies for CVDs.
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