PCSK9 inhibitors as safer therapeutics for atherosclerotic cardiovascular disease (ASCVD): Pharmacophore design and molecular dynamics analysis

被引:5
作者
Kehinde, Ibrahim O. [1 ,2 ]
Akawa, Oluwole [2 ]
Adewumi, Adeniyi T. [3 ]
Rabbad, Ali H. [1 ]
Soliman, Mahmoud E. S. [1 ]
机构
[1] Univ KwaZulu Natal, Sch Hlth Sci, Mol Biocomputat & Drug Design Lab, Westville Campus, ZA-4001 Durban, South Africa
[2] Afe Babalola Univ, Coll Pharm, Dept Pharmaceut & Med Chem, Ado Ekiti, Nigeria
[3] Univ South Africa, Dept Life & Consumer Sci, Florida Campus, Johannesburg, South Africa
关键词
binding free energy (MMGBSA); low-density lipoprotein cholesterol (LDLC); per-residue energy decomposition; pharmacophore; proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors; structural based virtual screening (SBVS); ORAL BIOAVAILABILITY; DRUG DISCOVERY; LDL RECEPTOR; PROTEIN; IDENTIFICATION; DEGRADATION; DOMAIN; ANTIBODIES; MUTATIONS; VARIANTS;
D O I
10.1002/jcb.30581
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all-atoms MD simulations and MMGBSA-based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of -33.39 and -63.51, respectively, against -27.97 of control. The final molecules showed suitable drug-likeness, non-mutagenesis, permeability, and high solubility values. The C-alpha atoms root mean square deviation and root mean square fluctuation of the bound-PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.
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页数:14
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