Dynamics of allosteric modulation of lymphocyte function associated antigen-1 closure-open switch: unveiling the structural mechanisms associated with outside-in signaling activation

Abdullahi, Maryam; Olotu, Fisayo A.; Soliman, Mahmoud E. S.

doi:10.1007/s10529-017-2432-0

Cited by 13 publications

(8 citation statements)

References 29 publications

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“…Computational biology entails in silico investigation which is an essential arm of biotechnology focused at enhancing a deeper insight of biomolecular interactions in order to address cellular disease pathogenesis whilst having immense contribution towards design and development of possible therapeutic candidates (Abdullahi et al, 2017). Indeed, this technique have assisted in identifying lead compounds for various diseases (Aruleba et al, 2018;Shanmuga Priya et al, 2018;.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory potential of repurposed drugs against the SARS-CoV-2 main protease: a computational-aided approach

Fadaka

Aruleba

Sibuyi

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The exponential increase in cases and mortality of coronavirus disease (COVID-19) has called for a need to develop drugs to treat this infection. Using in silico and molecular docking approaches, this study investigated the inhibitory effects of Pradimicin A, Lamivudine, Plerixafor and Lopinavir against SARS-CoV-2 M pro. ADME/Tox of the ligands, pharmacophore hypothesis of the co-crystalized ligand and the receptor, and docking studies were carried out on different modules of Schrodinger (2019-4) Maestro v12.2. Among the ligands subjected to ADME/Tox by QikProp, Lamivudine demonstrated drug-like physico-chemical properties. A total of five pharmacophore binding sites (A3, A4, R9, R10, and R11) were predicted from the co-crystalized ligand and the binding cavity of the SARS-CoV-2 M pro. The docking result showed that Lopinavir and Lamivudine bind with a higher affinity and lower free energy than the standard ligand having a glide score of À9.2 kcal/mol and À5.3 kcal/mol, respectively. Plerixafor and Pradimicin A have a glide score of À3.7 kcal/mol and À2.4 kcal/mol, respectively, which is lower than the co-crystallized ligand with a glide score of À5.3 kcal/mol. Molecular dynamics confirmed that the ligands maintained their interaction with the protein with lower RMSD fluctuations over the trajectory period of 100 nsecs and that GLU166 residue is pivotal for binding. On the whole, present study specifies the repurposing aptitude of these molecules as inhibitors of SARS-CoV-2 M pro with higher binding scores and forms energetically stable complexes with M pro .

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Section: Discussionmentioning

confidence: 99%

Inhibitory potential of repurposed drugs against the SARS-CoV-2 main protease: a computational-aided approach

Fadaka

Aruleba

Sibuyi

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…The complexes, which include unbound, NAR-and NAR-7-O-G-bound CRMP-2, were further prepared and set up for 100 ns MD simulations using in-house protocols previously reported. [18,25,26] MD simulations were carried out using the Graphics Processing Unit (GPU) version of Particle Mesh Ewald Molecular Dynamics (PMEMD) engine in Amber 14 software package [27,28] and its integrated modules such as LEAP, to add hydrogen atoms and counter ions for neutralization at constant pH (cpH). [28,29] Likewise, the tleap module was used to generate topology files for the ligands, protein and ligand-protein complexes, while the FF14SB force field was used to define protein parameters.…”

Section: Introductionmentioning

confidence: 99%

Exploring the C‐Terminal Tail Dynamics: Structural and Molecular Perspectives into the Therapeutic Activities of Novel CRMP‐2 Inhibitors, Naringenin and Naringenin‐7‐O‐glucuronide, in the Treatment of Alzheimer's Disease

Lawal

Olotu

Agoni

et al. 2018

Chemistry & Biodiversity

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The collapsin response mediator protein (CRMP‐2) is hyperphosphorylated in Alzheimer's disease (AD). These phosphorylation events are mediated by specific kinase proteins, GSK3β and Cdk5, and occur at target phosphorylation sites majorly located at the C‐terminal tail of CRMP‐2. The abilities of naringenin (NAR) and naringenin‐7‐O‐glucuronide (NAR‐7‐O‐G) to selectively bind CRMP‐2 and reduce its phosphorylation have been previously demonstrated; the molecular interplay between these events remains unresolved. Using computational tools, we unravel the possible mechanisms by which these molecules disrupt CRMP‐2 phosphorylation. Structural and dynamic analyses revealed that while the C‐terminal tail of unbound CRMP‐2 was extended and subtly organized, notable conformational disarray and rigidity characterized this region when bound by NAR and NAR‐7‐O‐G. Consequentially, atomistic motions of constituent phosphorylation sites were restricted, indicative of structural occurrences that could distort the accessibility of interactive kinase proteins. A similar pattern was observed at a target phosphorylation site located in the globular domain of CRMP‐2. MM/PBSA analyses revealed that both compounds interacted favorably with CRMP‐2 while crucial residues that enhanced their selective binding include Glu353, Thr349, Lys254, Asp140 and Arg75. These structural insights provide mechanistic events that could contribute towards the structure‐based design of anti‐AD molecules which can bind CRMP2 selectively and alter its phosphorylation process.

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“…This was done by docking an activator, IBE667, to the I‐domain allosteric site of LFA‐1. This method has been previously described in our previous studies, resulting in the characteristic downward α‐7 helical pull that defines an active LFA‐1 state . Two‐dimensional structures of doxycycline, hamamelitanin, naringin, quercetin, and resveratrol were retrieved from PubChem database, followed by the optimization of their molecular geometry using a steepest descent algorithm and UFF force field on Avogadro 1.2.0 (The Avogadro project [open source], University of Pittsburgh, PA) .…”

Section: Methodsmentioning

confidence: 99%

“…This method has been previously described in our previous studies, resulting in the characteristic downward α-7 helical pull that defines an active LFA-1 state. 31,54 Two-dimensional structures of doxycycline, hamamelitanin, naringin, quercetin, and resveratrol were retrieved from PubChem database, followed by the optimization of their molecular geometry using a steepest descent algorithm and UFF force field on Avogadro 1.2.0 (The Avogadro project [open source], University of Pittsburgh, PA). 55 These were then docked, respectively, into the LtxA binding site (LBS) of active LFA-1 using Autodock Vina (Molecular Graphics Lab, The Scripps Research Institute, Florida, USA).…”

Section: Datasets and System Preparationmentioning

confidence: 99%

Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases

Abdullahi

Olotu

Soliman

2018

J of Cellular Biochemistry

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Aggregatibacter actinomycetemcomitans is a Gram-negative bacteria that has gained wide recognition for its causative role in the development of various immune diseases, which includes localized aggressive periodontitis. Its ability to evade host defense mechanisms is mediated by the secretion of leukotoxin (LtxA), which induces death of white blood cells (leukocytes) by specific binding to their surface-expressed leukocyte function-associated receptor (LFA-1) in its active state. Therapeutic compounds that interfere with this pathogenic process and abrogate A. actinomycetemcomitans virulence have been reported in literature. These include doxycycline, and more recently phytochemical compounds such as hamamelitanin, resveratrol, naringin, and quercetin. However, the question remains how do they work? Therefore, with the aid of computational tools, we explore the molecular mechanisms by which they possibly elicit their therapeutic functions. Molecular mechanics Poisson/Boltzmann surface area analyses revealed that these compounds bind favorably to active LFA-1 with high affinity and considerable stability, indicative of their ability to occupy the LtxA binding site (LBS) and prevent LtxA binding. The conformational transition of open LFA-1 to its closed state further describe the mechanistic activity of these compounds. In addition to notable reductions in structural mobility and flexibility, the burial of surface-exposed interactive side chains at the LBS was observed, an occurrence that could alter the complementary binding of LtxA. It is also important to mention that these occurrences were induced more prominently by the phytochemicals. We believe that these findings will enhance the scope of drug design and discovery for potent LtxA antagonists with improved activities and therapeutic efficacies in the treatment of virulent A. actinomycetemcomitans diseases.

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Dynamics of allosteric modulation of lymphocyte function associated antigen-1 closure-open switch: unveiling the structural mechanisms associated with outside-in signaling activation

Abstract: Allosteric binding of IBE-667, activated LFA-1 integrin as evidenced by residual motion at the MIDAS region which appears to be synergistically coordinated by the downward pull of the α7 helix.

Cited by 13 publications

References 29 publications

Inhibitory potential of repurposed drugs against the SARS-CoV-2 main protease: a computational-aided approach

Inhibitory potential of repurposed drugs against the SARS-CoV-2 main protease: a computational-aided approach

Exploring the C‐Terminal Tail Dynamics: Structural and Molecular Perspectives into the Therapeutic Activities of Novel CRMP‐2 Inhibitors, Naringenin and Naringenin‐7‐O‐glucuronide, in the Treatment of Alzheimer's Disease

Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases

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