In silico study of novel niclosamide derivatives, SARS-CoV-2 nonstructural proteins catalytic residue-targeting small molecules drug candidates

Bashir Lawal; Sheng-Kuang Tsai; Alexander T.H. Wu; Hsu-Shan Huang

Arabian Journal of Chemistry (May 2023)

In silico study of novel niclosamide derivatives, SARS-CoV-2 nonstructural proteins catalytic residue-targeting small molecules drug candidates

Bashir Lawal,
Sheng-Kuang Tsai,
Alexander T.H. Wu,
Hsu-Shan Huang

Affiliations

Bashir Lawal: UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
Sheng-Kuang Tsai: Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
Alexander T.H. Wu: TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; The Ph.D. Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Corresponding authors at: TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan (A.T.H. Wu). PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan (H.-S. Huang).
Hsu-Shan Huang: Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei 11031, Taiwan; Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Corresponding authors at: TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan (A.T.H. Wu). PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan (H.-S. Huang).

Journal volume & issue: Vol. 16, no. 5
p. 104654

Abstract

Read online

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated coronavirus disease 2019 (COVID-19) infection remains a global pandemic and health emergency with overwhelming social and economic impacts throughout the world. Therapeutics for COVID-19 are limited to only remdesivir; therefore, there is a need for combined, multidisciplinary efforts to develop new therapeutic molecules and explore the effectiveness of existing drugs against SARS-CoV-2. In the present study, we reported eight (SCOV-L-02, SCOV-L-09, SCOV-L-10, SCOV-L-11, SCOV-L-15, SCOV-L-18, SCOV-L-22, and SCOV-L-23) novel structurally related small-molecule derivatives of niclosamide (SCOV-L series) for their targeting potential against angiotensin-converting enzyme-2 (ACE2), type II transmembrane serine protease (TMPRSS2), and SARS-COV-2 nonstructural proteins (NSPs) including NSP5 (3CLpro), NSP3 (PLpro), and RdRp. Our correlation analysis suggested that ACE2 and TMPRSS2 modulate host immune response via regulation of immune-infiltrating cells at the site of tissue/organs entries. In addition, we identified some TMPRSS2 and ACE2 microRNAs target regulatory networks in SARS-CoV-2 infection and thus open up a new window for microRNAs-based therapy for the treatment of SARS-CoV-2 infection. Our in vitro study revealed that with the exception of SCOV-L-11 and SCOV-L-23 which were non-active, the SCOV-L series exhibited strict antiproliferative activities and non-cytotoxic effects against ACE2- and TMPRSS2-expressing cells. Our molecular docking for the analysis of receptor-ligand interactions revealed that SCOV-L series demonstrated high ligand binding efficacies (at higher levels than clinical drugs) against the ACE2, TMPRSS2, and SARS-COV-2 NSPs. SCOV-L-18, SCOV-L-15, and SCOV-L-09 were particularly found to exhibit strong binding affinities with three key SARS-CoV-2’s proteins: 3CLpro, PLpro, and RdRp. These compounds bind to the several catalytic residues of the proteins, and satisfied the criteria of drug-like candidates, having good adsorption, distribution, metabolism, excretion, and toxicity (ADMET) pharmacokinetic profile. Altogether, the present study suggests the therapeutic potential of SCOV-L series for preventing and managing SARs-COV-2 infection and are currently under detailed investigation in our lab.

Published in Arabian Journal of Chemistry

ISSN: 1878-5352 (Print)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Chemistry
Website: http://www.journals.elsevier.com/arabian-journal-of-chemistry/

About the journal

Abstract

Keywords