Structures and dynamics of peptide and peptidomimetic inhibitors bound to the NS2B-NS3 protease of the ZIKA virus

Abstract

Infections caused by the Zika virus (ZIKV) have detrimental effects on human health, in particular on infants. As no potent drug or vaccine is available to date to contain this viral disease, it is necessary to design inhibitors that can target the NS2B-NS3 protease of the ZIKV, which is mainly responsible for the proliferation of the virus inside the host cells . Here, molecular dynamics (MD) simulation and molecular mechanics energies combined with the generalized Born and surface area continuum solvation model (MM/GBSA) are used to understand the binding modes and stabilities of R, KR, KKR, WKR, WKKR, YKKR, and FKKR peptide inhibitors bound to the NS3-NS2B protease. The results are compared with the corresponding results obtained for covalent (compound 1) and non-covalent (compound 4*) peptidomimetic inhibitors . It is revealed that peptide inhibitors can bind strongly with the ZIKV protease with the ΔG_bind ranging from −12 kcal/mol to −73 kcal/mol. Among these peptides, YKKR is found to make the most stable complex with the protease and fully occupy the electrostatically active substrate binding site. Hence, it would inhibit the protease activities of ZIKV strongly. The residue-wise decomposition of ΔG_bind indicates that Asp75, Asp129, Tyr130, Ser135, Gly151, Asn152, Glys153, and Tyr161 of NS3 and Ser81, Asp83, and Phe84 of NS2B play a prominent role in the inhibitor binding. Therefore, any future design of inhibitors should be aimed to target these residues.

The activities of the NS2B-NS3 protease of the ZIKV can be inhibited by the peptide inhibitor YKKR.

Communicated by Ramaswamy H. Sarma

Keywords:

• Zika virus
• peptide inhibitors
• NS2B-NS3 protease
• covalent inhibitors
• MD-simulations

Acknowledgment

SP is thankful to the department of pharmaceuticals and NIPER, Kolkata for providing a Senior Research Fellowship and necessary computational resources. NRJ is thankful to the Council of Scientific and Industrial Research (CSIR, NewDelhi) for financial support.

Data and software availability

The percentage occupations of different interactions and the timeline representations of these Interactions and contacts between the inhibitor and protease are provided in the Supporting

Information (Figure S1–S19, supplementary material). The comparison of binding modes of YKKR and TGKR is provided in Figure S20 (supplementary material). The initial and final structures (in the PDB format) of each protein-peptide complex can be downloaded from https://github.com/suyashniper/Binding-of-Peptide-Inhibitors-to-the-NS2BNS3-Protease-of-the-ZIKA-Virus. The MD trajectory files of each complex can be obtained on request. The trial version of the Desmond 2018 program can be obtained from Schrodinger to validate and reproduce the results obtained herein.

Disclosure statement

No potential conflict of interest was reported by the author(s).