SARS-CoV-2 virus outbreak poses a major threat to humans worldwide due to its highly contagious nature. In this study, molecular docking, molecular dynamics, and structure-activity relationship are employed to assess the binding affinity and interaction of 76 prescription drugs against RNA dependent RNA polymerase (RdRp) and Main Protease (Mpro) of SARS-CoV-2. The RNA-dependent RNA polymerase is a vital enzyme of coronavirus replication/transcription complex whereas the main protease acts on the proteolysis of replicase polyproteins. Among 76 prescription antiviral drugs, four drugs (Raltegravir, Simeprevir, Cobicistat, and Daclatasvir) that are previously used for human immunodeficiency virus (HIV), hepatitis C virus (HCV), Ebola, and Marburg virus show higher binding energy and strong interaction with active sites of the receptor proteins. To explore the dynamic nature of the interaction, 100 ns molecular dynamics (MD) simulation is performed on the selected protein-drug complexes and apo-protein. Binding free energy of the selected drugs is performed by MM/PBSA. Besides docking and dynamics, partial least square (PLS) regression method is applied for the quantitative structure activity relationship to generate and predict the binding energy for drugs. PLS regression satisfactorily predicts the binding energy of the effective antiviral drugs compared to binding energy achieved from molecular docking with a precision of 85%. This study highly recommends researchers to screen these potential drugs in vitro and in vivo against SARS-CoV-2 for further validation of utility.
The disorder of thyroid gland development or thyroid dysgenesis (TH) accounts for 80-85% cases of congenital hypothyroidism (CH). Hence, the understanding of molecular etiology of TH is prerequisite. Mutations in TSHR gene is mostly associated with thyroid dysgenesis, prevent or disrupt normal development of the gland. The current study detects two nonsynonymous mutations (p.Ser508Leu, p.Asp727Glu) in transmembrane (TM)-region (Exon 10) of TSHR gene in 21 patients with dysgenesis by sequencing-based analysis. Later, transmembrane (TM)-region of TSHR protein is modelled by homology modeling. Transmembrane (TM)-region of TSHR protein is targeted by small molecules thyrogenic drugs, MS437 and MS438 to perceive the effect of mutations. The damaging effect in drug-protein complexes of mutants were envisaged by molecular docking and interactions. The binding affinity of wild type protein was much higher than the mutant cases for both of the ligands (MS437 and MS438). Molecular dynamics simulates dynamic behavior of wild type and mutant complexes. MS437-TSHR368-764MT2 and MS438-TSHR368-764MT1 show stable conformations in biological environments. Finally, PCA reveals structural and energy profile discrepancies. TSHR368-764MT1 exhibits much variations than TSHR368-764WT and TSHR368-764MT2, emphasizing more damaging pattern in TSHR368-764MT1. The study might be helpful to understand molecular etiology of thyroid dysgenesis (TH) exploring the mutational impact on TSHR protein to the interaction with agonists.
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