Mechanisms
Fragment-based drug design screens 61,600 molecular fragments to find a novel small-molecule inhibitor of the Lp(a) kringle domain (J Bioenerg Biomembr 2024)
Original title: Fragment-based drug design of novel inhibitors targeting lipoprotein (a) kringle domain KIV-10-mediated cardiovascular disease
Targeting the lipoprotein(a) kringle domain, recently identified as a druggable target for cardiovascular disease, the authors used a fragment-based drug design approach, screening a library of 61,600 fragments combined with MM/GBSA scoring, molecular dynamics simulation, and principal component analysis. Hybridising the best-performing fragments generated 249 novel hybrid molecules, of which 77 showed superior binding affinity (-7 kcal/mol or better) to the control compound AZ-02 (-6.9 kcal/mol). Among the top ten candidates, the lead compound BR1 achieved the best docking energy (-11.85 kcal/mol) and greater stability within the protein's ligand-binding site, with principal component analysis showing binding motion similar to the control compound and reduced protein mobility. ADMET analysis indicated favourable drug-like properties for BR1, with minimal violations of the Lipinski rules. This computational study identifies a promising novel small-molecule Lp(a) kringle domain inhibitor candidate, though preclinical and clinical evaluation is still needed to confirm its efficacy and safety.
Original 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.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.