Molecular mechanism of binding between a therapeutic <scp>RNA</scp> aptamer and its protein target <scp>VEGF</scp>: A molecular dynamics study

Kalathingal, Mahroof; Rhee, Young Min

doi:10.1002/jcc.27070

Cited by 9 publications

(7 citation statements)

References 44 publications

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“…According to Kalathingal et al, Macugen detects HBD through a conformational selection process. In contrast, HBD recognizes Macugen through an induced-fit mechanism with significant conformational changes in Macugen and essentially without any changes in the HBD structure [ 107 ].…”

Section: Aptamer Mediated Targeting Of Vegfmentioning

confidence: 99%

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

Mishra,

Chattaraj,

Mishra

et al. 2023

Pharmaceuticals

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Cancer is one of the diseases that causes a high mortality as it involves unregulated and abnormal cell growth proliferation that can manifest in any body region. One of the typical ovarian cancer symptoms is damage to the female reproductive system. The death rate can be reduced through early detection of the ovarian cancer. Promising probes that can detect ovarian cancer are suitable aptamers. Aptamers, i.e., so-called chemical antibodies, have a strong affinity for the target biomarker and can typically be identified starting from a random library of oligonucleotides. Compared with other probes, ovarian cancer targeting using aptamers has demonstrated superior detection effectiveness. Various aptamers have been selected to detect the ovarian tumor biomarker, vascular endothelial growth factor (VEGF). The present review highlights the development of particular aptamers that target VEGF and detect ovarian cancer at its earliest stages. The therapeutic efficacy of aptamers in ovarian cancer treatment is also discussed.

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Section: Aptamer Mediated Targeting Of Vegfmentioning

confidence: 99%

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

Mishra,

Chattaraj,

Mishra

et al. 2023

Pharmaceuticals

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show abstract

Section: Introductionmentioning

confidence: 99%

“…Up to now, significant research efforts have been directed toward discovering inhibitors targeting VEGF to prevent its binding to VEGFR [14]. Several VEGF inhibitors have currently been approved for anti-angiogenic treatment, such as Bevacizumab [15], Aflibercept [16], and Macugen [17]. Aptamers are short single-stranded DNA or RNA molecules used for the molecular recognition of targets with high affinity and specificity [18,19].…”

Section: Introductionmentioning

confidence: 99%

An Ensemble Docking Approach for Analyzing and Designing Aptamer Heterodimers Targeting VEGF165

Go,

Kalathingal,

Rhee

2024

IJMS

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Vascular endothelial growth factor 165 (VEGF165) is a prominent isoform of the VEGF-A protein that plays a crucial role in various angiogenesis-related diseases. It is homodimeric, and each of its monomers is composed of two domains connected by a flexible linker. DNA aptamers, which have emerged as potent therapeutic molecules for many proteins with high specificity and affinity, can also work for VEGF165. A DNA aptamer heterodimer composed of monomers of V7t1 and del5-1 connected by a flexible linker (V7t1:del5-1) exhibits a greater binding affinity with VEGF165 compared to either of the two monomers alone. Although the structure of the complex formed between the aptamer heterodimer and VEGF165 is unknown due to the highly flexible linkers, gaining structural information will still be valuable for future developments. Toward this end of accessing structural information, we adopt an ensemble docking approach here. We first obtain an ensemble of structures for both VEGF165 and the aptamer heterodimer by considering both small- and large-scale motions. We then proceed through an extraction process based on ensemble docking, molecular dynamics simulations, and binding free energy calculations to predict the structures of the VEGF165/V7t1:del5-1 complex. Through the same procedures, we reach a new aptamer heterodimer that bears a locked nucleic acid-modified counterpart of V7t1, namely RNV66:del5-1, which also binds well with VEGF165. We apply the same protocol to the monomeric units V7t1, RNV66, and del5-1 to target VEGF165. We observe that V7t1:del5-1 and RNV66:del5-1 show higher binding affinities with VEGF165 than any of the monomers, consistent with experiments that support the notion that aptamer heterodimers are more effective anti-VEGF165 aptamers than monomeric aptamers. Among the five different aptamers studied here, the newly designed RNV66:del5-1 shows the highest binding affinity with VEGF165. We expect that our ensemble docking approach can help in de novo designs of homo/heterodimeric anti-angiogenic drugs to target the homodimeric VEGF165.

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“…For revealing the process, adopting computational tactics will be helpful. Indeed, there have been tremendous recent advancements in various in-silico techniques and strategies to overcome the limitations of experiments [ 21 – 32 ]. Among the diverse approaches, for following how the TMD dimer changes in time, adopting molecular dynamics (MD) simulations will be a natural choice.…”

Section: Introductionmentioning

confidence: 99%

Elucidating activation and deactivation dynamics of VEGFR-2 transmembrane domain with coarse-grained molecular dynamics simulations

Kalathingal

Rhee

2023

PLoS ONE

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The vascular endothelial growth factor receptor 2 (VEGFR-2) is a member of receptor tyrosine kinases (RTKs) and is a dimeric membrane protein that functions as a primary regulator of angiogenesis. As is usual with RTKs, spatial alignment of its transmembrane domain (TMD) is essential toward VEGFR-2 activation. Experimentally, the helix rotations within TMD around their own helical axes are known to participate importantly toward the activation process in VEGFR-2, but the detailed dynamics of the interconversion between the active and inactive TMD forms have not been clearly elucidated at the molecular level. Here, we attempt to elucidate the process by using coarse grained (CG) molecular dynamics (MD) simulations. We observe that inactive dimeric TMD in separation is structurally stable over tens of microseconds, suggesting that TMD itself is passive and does not allow spontaneous signaling of VEGFR-2. By starting from the active conformation, we reveal the mechanism of TMD inactivation through analyzing the CG MD trajectories. We observe that interconversions between a left-handed overlay and a right-handed one are essential for the process of going from an active TMD structure to the inactive form. In addition, our simulations find that the helices can rotate properly when the overlaying structure of the helices interconverts and when the crossing angle of the two helices changes by larger than ~40 degrees. As the activation right after the ligand attachment on VEGFR-2 will take place in the reverse manner of this inactivation process, these structural aspects will also appear importantly for the activation process. The rather large change in helix configuration for activation also explains why VEGFR-2 rarely self-activate and how the activating ligand structurally drive the whole VEGFR-2. This mechanism of TMD activation / inactivation within VEGFR-2 may help in further understanding the overall activation processes of other RTKs.

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Molecular mechanism of binding between a therapeutic RNA aptamer and its protein target VEGF: A molecular dynamics study

Cited by 9 publications

References 44 publications

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

An Ensemble Docking Approach for Analyzing and Designing Aptamer Heterodimers Targeting VEGF165

Elucidating activation and deactivation dynamics of VEGFR-2 transmembrane domain with coarse-grained molecular dynamics simulations

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