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Fragment-based drug design of novel inhibitors targeting lipoprotein (a) kringle domain KIV-10-mediated cardiovascular disease

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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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Funding

This Project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. (G: 413-140-1442). The authors, therefore, acknowledge with thanks DSR for technical and financial support.

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Authors and Affiliations

  1. Department of Clinical Pharmacology Faculty of Medicine, King Abdulaziz University, Jeddah, 21589, Saudi Arabia

    Mohammed Alsieni, Ahmed Esmat & Mohammed A Bazuhair

  2. Centre of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia

    Mohammed A Bazuhair

  3. Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, 23589, Saudi Arabia

    Hisham N. Altayb

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  1. Mohammed Alsieni
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  2. Ahmed Esmat
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Contributions

M.A. and H.N.A.: conceptualization, super-vision, methodology, investigation, and funding acquisition; A.E.A: writing review and editing, software, bioinformatics analysis, datacuration, validation, resources, visualization, and original draft prepa-ration. M.A.B: writing review and editing, software, bioinformaticsanalysis. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Hisham N. Altayb.

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Alsieni, M., Esmat, A., Bazuhair, M.A. et al. Fragment-based drug design of novel inhibitors targeting lipoprotein (a) kringle domain KIV-10-mediated cardiovascular disease. J Bioenerg Biomembr (2024). https://doi.org/10.1007/s10863-024-10013-2

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