Molecular profiling of Neprilysin expression and its interactions with SARS-CoV-2 spike proteins to develop evidence base pharmacological approaches for therapeutic intervention

Abstract

Neprilysin due to its peptidase activity is involved in several physiological and pathological processes. Recently our group has reported the association of neprilysin with angiotensin-converting enzyme 2 (ACE2) network proteins which facilitate the entry of SARS-COV2 virus. The potential role of neprilysin beyond its peptidase activity is not known. Using the established sequence analysis and molecular docking tools, this study evaluated the molecular profile of neprilysin interaction with SARS-COV2 virus proteins. Human neprilysin protein showed a significant sequence similarity with SARS-COV2 spike protein, which was further confirmed by observation of considerable interaction in the molecular docking. Human neprilysin protein was also found to additionally interact with SARS-COV2 proteins facilitating virus replication. The potential of neprilysin inhibitors (Sacubitril and Sacubitrilat) to interfere with neprilysin and SARS-COV2 proteins interactions was assessed. The neprilysin inhibitors showed binding efficacy within therapeutically feasible concentration range (1 to 150 uM). This study while reporting a novel role of neprilysin as potential receptor for SARS-COV2 virus, highlights the merit in assessing clinical efficacy of neprilysin inhibitors for the management of SARS-COV2 infection.

Network Pharmacology analysis of orally bioavailable SARS-COV2 protease inhibitor shows synergistic targets to improve clinical efficacy

“…[7,12,16] In similar lines the a nity of PF32 against SARS-COV2 targets was also estimated as reported before. [12,16] Expression of PF32 targets in human tissues Protein expression of PF32 targets in various human tissues was assessed from the human protein atlas database (https://www.proteinatlas.org) on 6 th May 2020 as described before [17,18] .…”

“…[7,12] The PDB le of PF32 was generated using the Chimera software and used for the analysis of its molecular interactions (number of hydrogen bonds) with all its identi ed targets as reported before. [12][13][14][15] The reported a nity of homologous structure of PF32 with Fibroblast activation protein alpha (PDB ID IZ68) was used as reference and the a nity of the PF32 with its identi ed targets was predicted based on the differences in the ratio of hydrogen bonds compared to that of the reference standard as reported before. [7,12,16] In similar lines the a nity of PF32 against SARS-COV2 targets was also estimated as reported before.…”

“…[12][13][14][15] The reported a nity of homologous structure of PF32 with Fibroblast activation protein alpha (PDB ID IZ68) was used as reference and the a nity of the PF32 with its identi ed targets was predicted based on the differences in the ratio of hydrogen bonds compared to that of the reference standard as reported before. [7,12,16] In similar lines the a nity of PF32 against SARS-COV2 targets was also estimated as reported before. [12,16] Expression of PF32 targets in human tissues Protein expression of PF32 targets in various human tissues was assessed from the human protein atlas database (https://www.proteinatlas.org) on 6 th May 2020 as described before [17,18] .…”

Network Pharmacology Analysis of Orally Bioavailable SARS-CoV-2 Protease Inhibitor Shows Synergistic Targets to Improve Clinical Efficacy

“…The protein data bank (PDB; https://www.rcsb.org) was searched for the 3D structures of identified targets of PF32 and the data was processed as reported before. 7,12 The PDB file of PF32 was generated using the Chimera software and used for the analysis of its molecular interactions (number of hydrogen bonds) with all its identified targets as reported before. [12][13][14][15] The reported affinity of homologous structure of PF32 with Fibroblast activation protein alpha (PDB ID IZ68) was used as reference and the affinity of the PF32 with its identified targets was predicted based on the differences in the ratio of hydrogen bonds compared to that of the reference standard as reported before.…”

“…7,12 The PDB file of PF32 was generated using the Chimera software and used for the analysis of its molecular interactions (number of hydrogen bonds) with all its identified targets as reported before. [12][13][14][15] The reported affinity of homologous structure of PF32 with Fibroblast activation protein alpha (PDB ID IZ68) was used as reference and the affinity of the PF32 with its identified targets was predicted based on the differences in the ratio of hydrogen bonds compared to that of the reference standard as reported before. 7,12,16 In similar lines the affinity of PF32 against SARS-CoV-2 targets was also estimated as reported before.…”