Computational molecular docking and virtual screening revealed promising SARS-CoV-2 drugs

The pandemic of novel coronavirus disease 2019(COVID-19)has rampaged the world,with more than 58.4 million confirmed cases and over 1.38 million deaths across the world by 23 November 2020.There is an urgent need to identify effective drugs and vaccines to fight against the virus.Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)belongs to the family of coronaviruses consisting of four structural and 16 non-structural proteins(NSP).Three non-structural proteins,main protease(Mpro),papain-like protease(PLpro),and RNAdependent RNA polymerase(RdRp),are believed to have a crucial role in replication of the virus.We applied computational ligand-receptor binding modeling and performed comprehensive virtual screening on FDA-approved drugs against these three SARS-CoV-2 proteins using AutoDock Vina,Glide,and rDock.Our computational studies identified six novel ligands as potential inhibitors against SARS-CoV-2,including antiemetics rolapitant and ondansetron for Mpro;labetalol and levomefolic acid for PLpro;and leucal and antifungal natamycin for RdRp.Molecular dynamics simulation confirmed the stability of the ligand-protein complexes.The results of our analysis with some other suggested drugs indicated that chloroquine and hydroxychloroquine had high binding energy(low inhibitory effect)with all three proteins—Mpro,PLpro,and RdRp.In summary,our computational molecular docking approach and virtual screening identified some promising candidate SARS-CoV-2 inhibitors that may be considered for further clinical studies.

Exercise and Ion-Channel Remodeling in Vascular Smooth Muscle During Hypertension:Therapeutic Implications

Myogenic contraction of vascular smooth muscle cells(VSMCs)in resistance arteries and arterioles plays a critical role in regulating peripheral resistance.Ion channels expressed in VSMCs control ion influx or efflux from the plasma membrane and endoplasmic reticulum to regulate membrane potential,which contributes to the regulation of vascular tone.With the depolarization of VSMC membranes,an elevation of intracellular calcium ion(Ca^(2+))concentration is mediated by voltage-gated Ca^(2+)channels and can trigger a vasoconstrictive response.In addition,potassium ion(K^(+))efflux through K^(+)channels can hyperpolarize VSMCs,resulting in vasodilation.However,in the pathophysiological progression of diseases such as hypertension,VSMCs undergo a wide range of pathological changes,among them is"electrical remodeling",which refers to changes in ion channels.Under physiological or pathological conditions,exercise has a profound impact on the human body,and ion channels are an essential target of the beneficial adaptive responses.This review provides insight on the physi-ological function of ion channels in VSMCs,including Cav1.2 channels,voltage-gated K^(+)channels,large-conductance Ca^(2+)-activated K^(+)channels,and inward-rectifier K^(+)channels,and the changes of these ion channels during hypertension.Focus is given to the effects of exercise on these ion channels and its implications in disease treatment.