Theoretical Insights into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and In Silico Screening of Main Protease Inhibitors

Abstract

Corona virus disease (COVID-19) is a dangerous disease rapidly spreading all over the world today. Currently there are no treatment options for it. Drug repurposing studies explored the potency of antimalarial drugs, chloroquine and hydroxychloroquine, against SARS-CoV-2 virus. These drugs can inhibit the viral protease, called chymotrypsin-like cysteine protease, also known as Main protease (3CL pro ); hence, we studied the binding efficiencies of 4-aminoquinoline and 8-aminoquinoline analogs of chloroquine. Six compounds furnished better binding energies than chloroquine and hydroxychloroquine. The interactions with the active site residues especially with Cys145 and His41, which are involved in catalytic diad for proteolysis, make these compounds potent main protease inhibitors. A regression model correlating binding energy and the molecular descriptors for chloroquine analogs was generated with R 2 = 0.9039 and Q 2 = 0.8848. This model was used to screen new analogs of primaquine and molecules from the Asinex compound library. The docking and regression analysis showed these analogs to be more potent inhibitors of 3CL pro than hydroxychloroquine and primaquine. The molecular dynamic simulations of the hits were carried out to determine the binding stabilities. Finally, we propose four compounds that show drug likeness toward SARS-CoV-2 that can be further validated through in vitro and in vivo studies.

In silico identification of SARS-CoV-2 spike (S) protein–ACE2 complex inhibitors from eight Tecoma species and cultivars analyzed by LC-MS

“…10 Many research endeavors are now directed towards nding an effective therapy against COVID 19. [11][12][13][14][15][16][17][18] As an extension from our previous research work, 2,19,20 we conducted a screening for natural products that could possess potential anti-SARS actions, however with more focus on the plants reported to possess antiviral as well as antimalarial activities (compared to the antimalarial medication "chloroquine" with approved anti SARS-CoV activity 21 ). We found that among Tecoma species, T. undulata was reported to exhibit anti-HIV activity 22 and T. mollis possessed anti-malarial activity using chloroquine sensitive clones of Plasmodium falciparum.…”

MACHINE LEARNING APPROACHES TO IDENTIFY POTENTIAL DNA Gyr B INHIBITORS FOR MYCOBACTERIUM TUBERCULOSIS

“…Various models were built using GaussianProcess, Linear Regression, MLP, and SMOreg algorithms. have to be close and greater than 0.6 [28].…”

Advances in Pathogenesis, Progression, Potential Targets and Targeted Therapeutic Strategies in SARS-CoV-2-Induced COVID-19

“…The study found that the amino Cys145 residue in the catalytic pocket of 3CL pro is an effective target for exploring small molecular covalent inhibitors of SARS-CoV-2 and other coronaviruses ( 118 ). A fluorescence resonance energy transfer study found that the 8-aminoquinoline antimalarial drug tafenoquine can induce the transformation of 3CL pro to expose the hydrophobic pocket and promote the protein aggregation, ultimately reducing the activity of 3CL pro and repressing SARS-CoV-2 RNA replication with an IC 50 near 2.5 μmol/L, which is appropriately 1/4 that of hydroxychloroquine ( 119 ). Although Lopinavir-Ritonavir ( Kaletra ) was initially used in the treatment of SARS-CoV-2 because of its ability to block the replication of SARS-CoV and MERS by inhibiting 3CL pro , the latest research results do not support its use in the treatment of COVID-19 ( 120 ).…”