RESUMO
Severe acute respiratory syndrome coronavirus 2 and associated coronavirus disease 2019 is a newly identified human coronavirus has imposed a serious threat to global health. The rapid transmission of severe acute respiratory syndrome coronavirus 2 and its ability to spread in humans have prompted the development of new approaches for its treatment. Severe acute respiratory syndrome coronavirus 2 requires RNA-dependent RNA polymerases for life cycle propagation and Spike (S)-protein for attachment to the host cell surface receptors. The virus enters the human body with the assistance of a key functional host receptor dipeptidyl peptidase-4 primed by transmembrane serine protease 2 which are putative targets for drug development. We performed screening of 267 compounds from Curcuma longa L. (Zingiberaceae family) against the viral S-protein and RNA-dependent RNA polymerases and host receptor proteins dipeptidyl peptidase-4 and transmembrane serine protease 2 using in silico molecular docking. Compounds C1, ((4Z,6E)-1,5-dihydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-4,6-dien3-one) and C6 ((4Z,6E)-1,5-dihydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hepta-4,6-dien-3-one) exhibited tight binding to the S1 domain of the Spike protein than VE607 and with RNA-dependent RNA polymerase protein more effectively than ribavirin and remdesivir. These compounds also interacted with the human host proteins dipeptidyl peptidase-4 and transmembrane serine protease 2 with higher efficiency than standard inhibitors sitagliptin and camostat mesylate. The lead compounds showed favorable free binding energy for all the studied protein-ligand complexes in Molecular mechanics/Generalized born model and solvent accessibility analysis. Besides, other Curcuma longa compounds C14 and C23 exhibited almost similar potential against these target proteins. The structure based optimization and molecular docking studies have provided information on some lead Curcuma longa compounds with probability for advancement in preclinical research.
RESUMO
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is at present an emerging global public health crisis. Angiotensin converting enzyme 2 (ACE2) and trans-membrane protease serine 2 (TMPRSS2) are the two major host factors that contribute to the virulence of SARS-CoV-2 and pathogenesis of coronavirus disease-19 (COVID-19). Transmission of SARS-CoV-2 from animal to human is considered a rare event that necessarily requires strong evolutionary adaptations. Till date no other human cellular receptors are identified beside ACE2 for SARS-CoV-2 entry inside the human cell. Proteolytic cleavage of viral spike (S)-protein and ACE2 by TMPRSS2 began the entire host-pathogen interaction initiated with the physical binding of ACE2 to S-protein. SARS-CoV-2 S-protein binds to ACE2 with much higher affinity and stability than that of SARS-CoVs. Molecular interactions between ACE2-S and TMPRSS2-S are crucial and preciously mediated by specific residues. Structural stability, binding affinity and level of expression of these three interacting proteins are key susceptibility factors for COVID-19. Specific protein-protein interactions (PPI) are being identified that explains uniqueness of SARS-CoV-2 infection. Amino acid substitutions due to naturally occurring genetic polymorphisms potentially alter these PPIs and poses further clinical heterogeneity of COVID-19. Repurposing of several phytochemicals and approved drugs against ACE2, TMPRSS2 and S-protein have been proposed that could inhibit PPI between them. We have also identified some novel lead phytochemicals present in Azadirachta indica and Aloe barbadensis which could be utilized for further in vitro and in vivo anti-COVID-19 drug discovery. Uncovering details of ACE2-S and TMPRSS2-S interactions would further contribute to future research on COVID-19.