RESUMEN

The unprecedented global pandemic of COVID-19 has created a daunting scenario urging an immediate generation of therapeutic strategy. Interventions to curb the spread of viral infection primarily include setting targets against the virus. Here in this study we target S protein to obstruct the viral attachment and entry and also the M pro to prevent the viral replication. For this purpose, the interaction of S protein and M pro with phytocompounds, sanguinarine and eugenol, and their derivatives were studied using computational tools. Docking studies gave evidence that 8-hydroxydihydrosanguinarine (8-HDS), a derivative of sanguinarine, showed maximum binding affinity with both the targets. The binding energies of the ligand with S protein and M pro scored to be ΔGb -9.4 Kcal/mol and ΔGb -10.3 Kcal/mol, respectively. MD simulation studies depict that the phytocompound could effectively cause structural perturbations in the targets which would affect their functions. 8-Hydroxydihydrosanguinarine distorts the α-helix in the secondary structure of M pro and RBD site of S protein. Protein-protein interaction study in presence of 8-hydroxydihydrosanguinarine also corroborate the above findings which indicate that this polyphenol interferes in the coupling of S protein and ACE2. The alterations in protonation of M pro suggest that the protein structure undergoes significant structural changes at neutral pH. ADME property of 8-hydroxydihydrosanguinarine indicates this could be a potential drug. This makes the phyto-alkaloid a possible therapeutic molecule for anti COVID-19 drug design.

Asunto(s)

Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Humanos , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Antivirales/farmacología , Antivirales/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Piridonas

RESUMEN

The recent outbreak of the coronavirus (SARS-CoV2) is an unprecedented threat to human health and society across the globe. In this context, development of suitable interventions is the need of the hour. The viral spike protein (S Protein) and the cognate host cell receptor ACE2 can be considered as effective and appropriate targets for interventions. It is evident from the present computational study, that catechin and curcumin, not only exhibit strong binding affinity to viral S Protein and host receptor ACE2 but also to their complex (receptor-binding domain (RBD) of the spike protein of SARS-CoV2 and ACE2; RBD/ACE2-complex). The binding affinity values of catechin and curcumin for the S protein, ACE2 and RBD/ACE2-complex are - 10.5 and - 7.9 kcal/mol; - 8.9 and - 7.8 kcal/mol; and - 9.1 and - 7.6 kcal/mol, respectively. Curcumin directly binds to the receptor binding domain (RBD) of viral S Protein. Molecular simulation study over a period of 100 ns further substantiates that such interaction within RBD site of S Protein occurs during 40-100 ns out of 100 ns simulation trajectory. Contrary to this, catechin binds with amino acid residues present near the RBD site of S Protein and causes fluctuation in the amino acid residues of the RBD and its near proximity. Both catechin and curcumin bind the interface of 'RBD/ACE2-complex' and intervene in causing fluctuation of the alpha helices and beta-strands of the protein complex. Protein-protein interaction studies in presence of curcumin or catechin also corroborate the above findings suggesting the efficacy of these two polyphenols in hindering the formation of S Protein-ACE2 complex. In conclusion, this computational study for the first time predicts the possibility of above two polyphenols for therapeutic strategy against SARS-CoV2.

Asunto(s)

Enzima Convertidora de Angiotensina 2/metabolismo , Catequina/metabolismo , Curcumina/metabolismo , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/metabolismo , Secuencia de Aminoácidos , Enzima Convertidora de Angiotensina 2/química , Sitios de Unión , COVID-19/metabolismo , COVID-19/virología , Catequina/química , Catequina/farmacología , Membrana Celular/metabolismo , Biología Computacional/métodos , Curcumina/química , Curcumina/farmacología , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Dominios Proteicos , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Tratamiento Farmacológico de COVID-19

RESUMEN

Squamous cell carcinoma, which is a malignant tumor of the squamous epithelium, has been a major cause of morbidity and mortality worldwide. It is a major health problem across the world and among the most common cancers seen in both Indian men and women as can be gauged from the records of the National Cancer Registry Programme. This study was undertaken to analyze the spectrum of squamous cell carcinoma cases presenting at M.Y. Hospital, Indore, during 2 years between 2007 and 2008, to understand the morphological patterns of squamous cell carcinoma lesions and classify them into morphological categories given by International Classification of Diseases for Oncology (ICD-O, third edition), to analyze the anatomical site distribution pattern of squamous cell carcinoma lesions and categorize them in topographical classes given by ICD-O. Over a 2-year period, 959 cases were retrieved from the files of histopathology laboratory, department of pathology, M.G.M. Medical College, Indore. Out of total 959 cases, the maximum cases-290 (30.24 %)-of squamous cell carcinoma were found between the fourth and fifth decades of life. The frequency of squamous cell carcinoma in patients older than 30 years was 96.35 %, while in cases of less than 30 years, it was 03.65 %. Most of the reported cases of squamous cell carcinoma included invasive types (i.e., 94.3 %). Cases with distant metastasis constituted 4.7 %, while only 1 % were noninvasive or in situ. The frequency of squamous cell carcinoma presenting at our institution was highest among those involving the lip, oral cavity, and pharynx (56.50 %), followed by those involving female genital organs (30.24 %). The respective involvement of skin, digestive organs, and respiratory systems was 4.70, 3.86, and 2.40 % in decreasing order of frequency. Frequency was least (1.05 %) among the cases reported to show metastatic deposits of squamous cell carcinoma in lymph nodes. Regarding the topographical spectrum, the maximum number of cases (26.07 %) of squamous cell carcinoma encountered belonged to ICD-O category C-53 (i.e., cervix). Among the morphological categories, the most frequently encountered was that of squamous cell carcinoma, keratinizing (35.2 %).