Dynamics of the personalities of PCSK9 on missense variants (rs505151 and rs562556) from elderly cohort studies in Brazil

Lopes, Vitor Galvão; Oliveira, Victor Fernandes de; Dati, Lívia Mendonça Munhoz; Naslavsky, Michel Satya; Ferreira, Gláucio Monteiro; Hirata, Mário Hiroyuki

doi:10.1080/07391102.2023.2191140

Cited by 4 publications

(1 citation statement)

References 47 publications

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“…energy to the complex. Individual amino acids provided a significant amount of energy towards the interaction with the ligands 57 . Although ARG381 (−5.428 kcal/mol) has the lowest van der Waals (vdW) energy contribution but has the largest electrostatic and total energy contributions to the inhibitor's binding whereas ARG399 has the highest vdW contribution to the interaction.…”

Section: Resultsmentioning

confidence: 99%

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

Kehinde,

Akawa,

Adewumi

et al. 2024

J of Cellular Biochemistry

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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‐α 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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Section: Resultsmentioning

confidence: 99%

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

Kehinde,

Akawa,

Adewumi

et al. 2024

J of Cellular Biochemistry

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Active and allosteric site binding MM-QM studies of Methylidene tetracyclo derivative in PCSK9 protein intended to make a safe antilipidemic agent

Irfan,

Vaithyanathan,

Anandaram

et al. 2023

Journal of Biomolecular Structure and Dynamics

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Active and Allosteric Site Binding MOLECULAR MECHANICS-QUANTUM MECHANICS studies of STEVIOSIDE Derivative in PCSK9 Protein Intended to provide a safe Antilipidemic agent

Navabshan¹,

Vaithyanathan²,

Anandaram

et al. 2023

Preprint

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Interaction of low-density lipoprotein receptors with proprotein convertase subtilisin/ kexin type 9 (PCSK9) plays a vital role in causing atherosclerosis. It is the hidden precursor of clinical myocardial infarction (MI), stroke, CVD and estimates 60% of deaths worldwide. The current need is to design small molecules to prevent the interaction between PCSK9 with LDL receptors. This study aims to evaluate the PCSK9 antagonistic effect of a derivative of Stevioside ( also referred as Methylidene tetracyclo derivative) and atorvastatin. Also, a comparative study was performed to analyze the binding interaction of molecules inside the active and allosteric sites of PCSK9. The RCSB downloaded protein 7S5H and above said ligands were optimized to the local minima energy level and docked inside the active and allosteric sites. The stability of non-bonded interaction of complex was analyzed using Desmond MD simulation studies. The results of docking showed that the Methylidene tetracyclo molecule possesses a two-fold higher affinity of -10.159 kcal/mol in the active site and -10.824 kcal/mol in the allosteric site. The Phe377 amino acid made the Methylidene tetracyclo molecule orient inside the active site. Nine H-bonds with 5 amino acids of allosteric site increase the binding affinity compared to Atorvastatin. The MD simulation studies exposed that the nonbonded interaction of Methylidene tetracyclo molecule was stable throughout 100ns. This confirms the Methylidene tetracyclo molecule will be the better hit as well as the lead molecule to inhibit PCSK9 protein.

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Dynamics of the personalities of PCSK9 on missense variants (rs505151 and rs562556) from elderly cohort studies in Brazil

Cited by 4 publications

References 47 publications

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

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

Active and allosteric site binding MM-QM studies of Methylidene tetracyclo derivative in PCSK9 protein intended to make a safe antilipidemic agent

Active and Allosteric Site Binding MOLECULAR MECHANICS-QUANTUM MECHANICS studies of STEVIOSIDE Derivative in PCSK9 Protein Intended to provide a safe Antilipidemic agent

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