RESUMEN
Congruous coronavirus drug targets and analogous lead molecules must be identified as quickly as possible to produce antiviral therapeutics against human coronavirus (HCoV SARS 3CLpro) infections. In the present communication, we bear recognized a HIT candidate for HCoV SARS 3CLpro inhibition. Four Parametric GA-MLR primarily based QSAR model (R2:0.84, R2adj:0.82, Q2loo: 0.78) was once promoted using a dataset over 37 structurally diverse molecules along QSAR based virtual screening (QSAR-VS), molecular docking (MD) then molecular dynamic simulation (MDS) analysis and MMGBSA calculations. The QSAR-based virtual screening was utilized to find novel lead molecules from an in-house database of 100 molecules. The QSAR-vS successfully offered a hit molecule with an improved PEC50 value from 5.88 to 6.08. The benzene ring, phenyl ring, amide oxygen and nitrogen, and other important pharmacophoric sites are revealed via MD and MDS studies. Ile164, Pro188, Leu190, Thr25, His41, Asn46, Thr47, Ser49, Asn189, Gln191, Thr47, and Asn141 are among the key amino acid residues in the S1 and S2 pocket. A stable complex of a lead molecule with the HCoV SARS 3CLpro was discovered using MDS. MM-GBSA calculations resulted from MD simulation results well supported with the binding energies calculated from the docking results. The results of this study can be exploited to develop a novel antiviral target, such as an HCoV SARS 3CLpro Inhibitor.
RESUMEN
BACKGROUND: Sofosbuvir (SOF), a direct acting antiviral, has revolutionized the treatment of chronic Hepatitis C Virus (HCV) infection. However, data is scarce about efficacy of SOF plus Ribavarin (RBV) in Indian patients with decompensated cirrhosis. We evaluated the efficacy of SOF plus RBV in decompensated cirrhosis, and compared the outcome with compensated cirrhosis and non-cirrhotics. PATIENTS AND METHODS: Consecutive decompensated cirrhotic patients of chronic HCV with detectable HCV RNA were treated with 24-week course of SOF (400 mg) plus weight based RBV. Sustained Virological Response (SVR), Child Turcotte Pugh (CTP) and Model for Endstage Liver Disease (MELD) scores were assessed at 36 weeks (i.e. 12 weeks after completion of therapy). Non-cirrhotic chronic hepatitis C patients and patients with compensated cirrhosis treated with SOF plus RBV during the same period were used as controls. During the period of this study ledipasvir and daclatasvir were not available in India. RESULTS: A total of 47 patients [median age 50 (29-82) years, 64% males] with decompensated cirrhosis were included as 'cases' in the study; while, 27 patients with compensated cirrhosis and 29 patients with chronic hepatitis were included as 'controls'. Age, gender, HCV RNA levels, and genotype distribution were similar in cases and controls. The median CTP and MELD scores of cases were 8 (7-12) and 13 (6-25), respectively. Among cases 39 (83%) could complete the therapy, while 1 (2%) was intolerant and 7 (15%) died before completion of therapy. End of Treatment Response (ETR) was achieved in 37/39 (95%) cases. Of these, another 3 died before SVR, and 7 failed to achieve SVR, thus 27/34 (79%) could achieve SVR. Thus according to intention-to-treat analysis, only 27/47 (57%) cases could achieve SVR. In comparison, 24/28 (86%) compensated cirrhotics and 27/28 (96%) of chronic hepatitis achieved SVR. There was a significant improvement in mean CTP score in cases who achieved SVR (P < 0.01) compared to those who did not achieve SVR/ETR. On multivariate analysis the only independent factor influencing successful outcome patients was a serum albumin >3.5 g/dL. CONCLUSIONS: A 24-week course of SOF plus ribavirin in decompensated HCV cirrhosis could lead to SVR in only 57% of patients. The failure of therapy in 43% patients was either due to non-response, intolerance, or death. A serum albumin of more than 3.5 is associated with success of antiviral therapy. Thus an early initiation of antiviral therapy is recommended before decompensation sets in as it precludes successful outcome.