Page 137 - GPD-4-2

Gene & Protein in Disease Binding of 11q to DENV and WNV proteases

(Table 1), indicating a strong and energetically favorable These results are in agreement with earlier biochemical
binding affinity. Per residue decomposition of binding free studies, where 11q was found to be safe for humans. 33
energy suggests that T132, followed by Y161, substantially
contributes to the binding free energy (Figure 6B). 4. Conclusion
If we compare the docking scores and binding free The NS2B–NS3 proteases of DENV and WNV are
energies of different complexes studied herein (Table 1), important targets for antiviral drug discovery. The present
it is evident that 11q binds more favorably to the DENV study highlights that 11q can bind to the substrate active
protease than the WNV protease. The binding affinity site of the NS2B–NS3 proteases of the DENV and WNV
of DENV–11q protease is similar to that of ZIKV–11q firmly, with binding free energies ranging between ~−13.13
protease complex (Table 1). This implies that 11q would ± 2.56 kcal/mol and −15.80 ± 3.34 kcal/mol. The binding
bind to DENV protease as strongly as the ZIKV protease, of 11q was found to be mainly stabilized by stacking
which in turn will be more stable than the known protease interactions involving Y161 and H51 and hydrogen
inhibitor SYC–1307. In an earlier study, an antiviral bonding interactions involving S135, G133, and T132.
34
22
drug, ritonavir, was shown to bind to the proteases of Notably, despite identical structures and sequences of the
DENV and WNV with binding free energies of −11.51 active site of the DENV and WNV proteases, their protein
± 2.82 kcal/mol and −7.43 ± 2.16 kcal/mol, respectively. dynamics were distinct. Because of this, 11q adopted
Similarly, another antiviral drug, paritaprevir, was shown different conformations in the DENV and WNV protease
to bind to DENV and WNV proteases with binding free active sites. Remarkably, the binding affinity of 11q was
energies of −12.76 ± 2.91 kcal/mol and −17.3 ± 2.55 found to be identical for ZIKV and DENV proteases, which
kcal/mol, respectively. These results indicate that 11q is significantly higher than that of SYC–1307. The binding
22
would form complexes with DENV protease that are about affinity of 11q bound to WNV was also higher than that of
4 kcal/mol more stable than those formed with ritonavir, SYC–1307 bound to the ZIKV protease. Due to its higher
and about 3 kcal/mol more stable than with paritaprevir binding affinity and excellent bioavailability, 11q is likely
(Table 1). Similarly, 11q binds to the WNV protease with to act as a pan-antiviral against DENV, WNV, and ZIKV
a binding free energy approximately 6 kcal/mol more infections. However, biochemical evaluations of protease
activities in the presence of 11q are necessary to gain more
favorable than ritonavir, but about 4 kcal/mol less favorable insights into its inhibitory potential.
than paritaprevir (Table 1). Therefore, 11q would serve as
a better inhibitor of DENV protease than ritonavir and Acknowledgments
22
paritaprevir. However, although 11q would be a more
efficient inhibitor of WNV protease than ritonavir, it would None.
be less effective than paritaprevir. 22 Funding
In an earlier study, the drug-likeness of 11q was
assessed by calculating all parameters defined by Nihar Ranjan Jena is thankful to the Council of Scientific
Lipinski’s Rule of 5. It was found that the computed and Industrial Research (CSIR, New Delhi) and the Science
34
and Engineering Research Board (SERB, New Delhi) for
molecular weight, lipophilicity (measured by logP), and the financial support (Grant No. for CSIR: 01/3061/21/
the number of hydrogen bond donors and acceptors of EMR-II and Grant No. for SERB: EMR/2016/005110).
34
11q did not violate Lipinski’s Rule of 5. Similarly, the
pharmacokinetic properties of 11q were computed using Conflict of interest
absorption, distribution, metabolism, and excretion
properties. Notably, the gastrointestinal absorption, The authors declare no conflicts of interest.
blood–brain barrier permeability, potential interactions Author contributions
with key cytochrome P450 enzymes, and activity of efflux
transporters are factors in predicting drug metabolism Conceptualization: Nihar Ranjan Jena
and safety. It was found that 11q exhibits favorable Investigation: Ramprakash Yadav
gastrointestinal absorption, limited blood–brain barrier Methodology: Nihar Ranjan Jena
penetration, no central nervous system-related side effects, Supervision: Nihar Ranjan Jena
and no significant inhibitory interaction with major Writing – original draft: All authors
cytochrome P450 isoforms. The combined absorption, Writing – review & editing: All authors
34
distribution, metabolism, excretion, and toxicity profile
indicates that 11q may act as a promising and safe Ethics approval and consent to participate
therapeutic candidate against DENV and WNV infections. Not applicable.

Volume 4 Issue 2 (2025) 8 doi: 10.36922/gpd.8293