key: cord-326320-flfrdrbi
authors: Choudhary, Shalki; Silakari, Om
title: Scaffold morphing of arbidol (umifenovir) in search of multi-targeting therapy halting the interaction of SARS-CoV-2 with ACE2 and other proteases involved in COVID-19
date: 2020-08-29
journal: Virus Res
DOI: 10.1016/j.virusres.2020.198146
sha: 
doc_id: 326320
cord_uid: flfrdrbi

The rapid emergence of a novel coronavirus, SARS-coronavirus 2 (SARS-CoV-2), originated from Wuhan, China, imposed a global health emergency. Angiotensin-converting enzyme 2 (ACE2) receptor serves as an entry point for this deadly virus while the proteases like furin, transmembrane protease serine 2 (TMPRSS2) and 3 chymotrypsin-like protease (3CLpro) are involved in the further processing and replication of SARS-CoV-2. The interaction of SP with ACE2 and these proteases results in the SARS-CoV-2 invasion and fast epidemic spread. The small molecular inhibitors are reported to limit the interaction of SP with ACE2 and other proteases. Arbidol, a membrane fusion inhibitor approved for influenza virus is currently undergoing clinical trials against COVID-19. In this context, we report some analogues of arbidol designed by scaffold morphing and structure-based designing approaches with a superior therapeutic profile. The representative compounds A_BR4, A_BR9, A_BR18, A_BR22 and A_BR28 restricted the interaction of SARS-CoV-2 SP with ACE2 and host proteases furin and TMPRSS2. For 3CLPro, Compounds A_BR5, A_BR6, A_BR9 and A_BR18 exhibited high binding affinity, docking score and key residue interactions. Overall, A_BR18 and A_BR28 demonstrated multi-targeting potential against all the targets. Among these top-scoring molecules A_BR9, A_BR18, A_BR22 and A_BR28 were predicted to confer favorable ADME properties.

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing medical health emergency worldwide (Sohrabi et al., 2020) . This outbreak was initially originated from Wuhan, Hubei, China in December 2019 and rapidly expanded to almost 187 countries throughout the globe (Wang et al., 2020a) . On March 11, 2020, world health organization (WHO) declared the COVID-19 situation as pandemic as the confirmed positive cases approached 2 million people with an estimated 8000 deaths (Bedford et al., 2020) . As of June 24, 2020, a total of 92,78,515 cases with 4,76840 deaths have been recorded globally due to . Amid this pandemic, researchers and scientists around the globe are engaged in finding an effective treatment for this deadly virus. Currently, there is no effective drug targeting SARS-CoV-2, the causative agent of COVID-19, however, various drugs from different categories are undergoing clinical trials for drug repurposing (Ciliberto et al., 2020; Lythgoe and Middleton, 2020; Rosa and Santos, 2020) . Most of these drugs belong to antiviral (Mevada et al., 2020) , antimalarial , and immunomodulatory (Zhao, 2020) categories.

For searching an effective therapy, one should understand the pathophysiology of SARS-CoV-2 infection and its transmission from one person to another at the molecular level. Here, instead of describing the detailed molecular biology of the virus, we are briefly discussing the key molecular events which we explored in this designing strategy. The entry of coronavirus in the host cell depends on the binding of the viral spike proteins (SP) to cellular receptors and its priming by host cell proteases (Hoffmann et al., 2020) . SARS-CoV-2 uses the ACE2 receptor to enter into the host cell by complexing with SP and further, transmembrane proteases furin and TMPRSS2 to cause the proteolytic activation of SP (Zhou et al., 2020) . Thus, the invasion of the virus into the host cell mainly explores the ACE2 receptor and two more proteolytic enzymes furin and TMPRSS2 (Bestle et al., 2020) .

Briefly, the binding of the S1 domain of SP to the enzymatic domain of ACE2 present on the cell surface results in endocytosis and translocation of both the virus as well as enzyme into endosomes located within the cells (Lan et al., 2020) . This entry process also requires priming of SP which is mediated by the host proteases furin and TMPRSS2. The S1/S2 domain of SP in newly emerged coronavirus (SARS-CoV-2) harbor potential protease cleavage site (PCS), NSPRRAR ^ SVA (^ is cleavage site), having four distinct amino acids (in bold), which is absent in SARS-CoV of the same clade and thereby became a keyhole for viral invasion J o u r n a l P r e -p r o o f (Wang et al., 2020b) . These mutations have given the ability to a virus to infect a wider variety of tissues in the body.

Followed by ACE2 mediated viral attachment and transmembrane proteases (furin, TMPRSS2) mediated membrane fusion and endocytosis, this deadly virus is further processed for replication by viral proteases. Viral protease 3CLpro (M Pro ) with the help of papain-like protease (PLPro) is mainly involved in proteolysis and plays an important role in processing the polyproteins that are translated from the viral RNA . Essentially, the interaction of SP with ACE2, its priming by host proteases (furin, TMPRSS2) at PCS and replication by viral protease 3CLpro is the primary reason for SARS-CoV-2 invasion and fast epidemic spread (McKee et al., 2020) . All the molecular processes are displayed in Figure 1 . Various studies suggested that the compounds restricting the interaction of SP with ACE2 and inhibit the key protease enzymes could make a highly effective treatment to prevent COVID-19.

Arbidol (also known as umifenovir), an effective antiviral drug approved for influenza virus is currently ongoing clinical trials against COVID-19 (Chen et al., 2020; Lythgoe and Middleton, 2020; Wilkinson and Dahly, 2020; Zhu et al., 2020) . This broad-spectrum antiviral drug has shown promising results in different pre-clinical and clinical trials (Blaising et al., 2014; Huang et al., 2020; Lythgoe and Middleton, 2020; Pecheur et al., 2007) . Arbidol is a non-nucleoside membrane fusion inhibitor that prevents the interaction of the influenza virus to the host cell. As per the recent report, the binding mode of arbidol to SARS-CoV-2 SP is similar to that of influenza virus haemagglutinin (HA) (Vankadari, 2020) . It is evident from the literature reports that various substituents of arbidol play a different role in its antiviral activity. Previous studies discussed the structure-activity relationship (SAR) of arbidol in broad-spectrum antiviral activity (Di Mola et al., 2014; Wright et al., 2017) . SAR profile of arbidol suggests that the indole core and thiophenyl group present on it are crucial for the activity while the presence of bromine on the indole backbone does not have any significant effect on antiviral activity. Besides, the replacement of the remaining functionalities may increase or decrease the activity depending upon the type of virus considered. Briefly, the indole ring and thiophenyl group of arbidol are buried inside the hydrophobic cavity of influenza virus HA whereas, polar groups such as hydroxyl and bromine are exposed to solvent. This way, through an induced fit mechanism, arbidol causes the conformational changes in the cavity that in turn break the existing salt-bridge between the virus and host membrane and form a new one (Kadam and Wilson, 2017; Pecheur et al., 2007) . Within this frame of reference, we report some analogues of arbidol against SARS-CoV-2, designed by scaffold morphing and structure-based drug designing approaches. Scaffold J o u r n a l P r e -p r o o f 6 morphing is a unique medicinal chemistry tool utilized for rational drug designing by a gradual transformation in the parent molecule to develop novel molecules with a potentially improved therapeutic profile. This drug designing strategy takes into consideration the synthetic feasibility of new scaffolds and is essentially a chemistry-driven approach (Shandil et al., 2019) . We utilized the scaffold morphing approach in combination with molecular docking and MM/GBSA (molecular mechanics generalized Born and surface area) calculation to identify better therapy than arbidol. The multi-targeting potential of generated analogues was explored against various targets involved in the pathogenesis of COVID-19 including SARS-CoV-2 SP, ACE2, furin, TMPRSS2 (in viral attachment) and 3CLPro (in viral replication). Considering the current public health emergency, this study is aimed to identify the potential analogues of arbidol which can possibly manage the epidemic spread of SARS-CoV-2. 

Scaffold morphing is a drug designing approach to improve the synthetic feasibility, potency, and drug-likeness of molecules by gradually modifying its structural features. This method provides a new chemical space the lead molecule that may in turn contribute to improving the overall therapeutic profile of that molecule (Langdon et al., 2010) . For scaffold morphing, the bio-isosteric replacement method was adopted that involves swapping the functional groups of a molecule with their bio-isosteres and improve the potency as well as the pharmacokinetic profile of that particular molecule (Dick and Cocklin, 2020) . In this study, the bio-isosteric transformation in arbidol was done using a freely available web server MolOpt (Shan and Ji, 2019) . MolOpt is a recently developed web tool for in-silico drug designing. This web server automatically generates several analogues based on bio-isosteric transformation rules derived from data mining, deep generative models and similarity comparison. In current study, the rule of data mining was utilized for bio-isosteric replacement. The generated set of molecules is then ranked based on their synthetic possibility. Adopting this inbuilt protocol of MolOpt, the six replacement sites of arbidol, as suggested by this web server, were explored. The generated analogues of arbidol corresponding to each replacement site were sorted based on their synthetic possibility. Synthetic accessibility score ranges from 1 (very easy) to 10 (very difficult). A cutoff value of 3 was used for the screening of compounds based on synthetic possibility and topranked molecules were submitted to structure-guided drug binding analysis such as molecular docking studies.

Molecular docking is a structure-based drug designing approach used to find out the best orientation and key interactions between ligand and receptor. Molecular docking experiments were performed on maestro molecular modeling interface (Schrödinger Suite, LLC, NY) (Release, 2019) . The 3D X-ray crystal structures of SARS-CoV-2 SP receptor-binding domain in complex with its receptor ACE2 (PDB ID: 6LZG, resolution 2.5 Å), human furin (PDB ID: 5MIM, resolution 1.9 Å) and main protease 3CLPro (PDB ID: 6LU7, resolution 2.16 Å) were retrieved from the Protein Data Bank accessed at the URL (http://www.rscb.org/pdb). Since the X-ray crystal structure of TMPRSS2 was not available, a homology model ( The 3D chemical structure of arbidol was extracted from the PubChem database while the SMILES notations of arbidol analogues (generated by MolOpt webserver) were used to build their 3D structures. LigPrep module of Schrodinger was used to prepare ligands by adding hydrogen, removing salt and ionizing at pH 7 ± 0.5 (Choudhary and Silakari, 2019) . Since arbidol is reported to impair the membrane fusion of viruses under low pH in the endosome, the docking analysis with proteins involved in viral entry (ACE2 and Spike protein) was performed at pH 5 ± 0.5 (at which arbidol is reported to show better fusion inhibition) (Kadam and Wilson, 2017; Leneva et al., 2009) . Geometry optimization and energy minimization were performed under the OPLS_3 force field to generate low energy conformers using standard energy function of molecular mechanics with RMSD cut off 0.01 Ǻ (Shah et al., 2020) . The prepared and minimized molecules were then docked into the grid generated from the accurately prepared protein structures.

Proteins were prepared using the 'protein preparation wizard' tool of maestro interface by following preprocess, review and modify, optimization and finally minimization under OPLS_3 force field. During protein preparation, hydrogens were added, bond order was assigned and missing loops and side chains were updated using prime. Waters molecules were removed within 5Å of het groups to avoid unnecessary hindrance during docking. The receptor grids were generated within the 20 Å radiuses around the co-crystallized ligands using 'receptor grid generation' option available with Glide. The proteins in which the co-crystallized ligand was not available, SiteMap module of maestro was used to predict the putative binding sites and grids with a cubic box of 10 Ǻ × 10 Ǻ × 10 Ǻ were generated around the top-ranked sites (Schrödinger, 2013) . The van der Waals scaling factor of 1.00 and partial charge cutoff value of 0.25 were selected. For ligand atoms, these cutoff values were kept as 0.80 and 0.15 respectively.

The docking analysis was performed using extra precision (XP) docking option which predicts the binding modes and their Glide XP G-score (Pathak et al., 2020) . A total of ten docking poses were generated corresponding to each ligand and the best poses were selected based on good Gscores and appropriate binding orientations. The docked poses were analyzed for the molecular interactions and the formation of hydrogen bonds between the ligand and the active site residues present in the hinge region.

To better understand the biological process, the ligand should bind to the protein in a specific manner. Therefore, the ligand-binding energies were calculated using the Prime MM-GBSA J o u r n a l P r e -p r o o f option of the Schrodinger software. MM-GBSA is a method to calculate the free binding energy of a ligand to its protein and is calculated in terms of the MM-GBSA score (Haider et al., 2011) .

The main contributory factors in MM-GBSA calculations are OPLS molecular mechanics energies (EMM), polar solvation through surface generalized born solvation model (GSGB), and a non-polar solvation term composed of the non-polar solvent accessible surface area and van der Waals interactions (Sun et al., 2014) . For a better representation of the solvent-accessible surface area, this method uses the Gaussian surface instead of a van der Waals surface and adopts the surface-generalized born model (Du et al., 2011) .

The MM-GBSA binding energy is calculated in terms of kcal/mol by using the equation:

MM-GBSA ΔGbind = ER: EL -EL -ER

Where ER: EL, EL, and ER are the prime energies of the optimized complex, free ligand and free receptor, respectively (Singh and Silakari, 2018) .

To investigate the pharmacokinetic profile of newly generated analogues, their ADME (Absorption, Distribution, Metabolism, and Excretion) properties were predicted using the QikProp program of the Schrödinger software (QikProp, 2015) . This provided an estimate of the physicochemical properties and the bioavailability of the compounds. Various parameters such as polar surface area (PSA), solvent accessible surface area (SASA), QPPCaco (predicted apparent Caco-2 cell permeability in nm/s, CNS activity (predicted central nervous system activity on a -2 (inactive) to +2 (active) scales). QPlogBB (predicted brain/blood partition coefficient), QPPMDCK (predicted apparent MDCK cell permeability in nm/s), QPlogS (predicted aqueous solubility), QPlogKhsa (prediction of binding to human serum albumin), and percent human oral absorption (predicted human oral absorption on 0-100% scale) were calculated. Among these parameters, Caco-2 cells are a model for the gut blood barrier and MDCK cells are considered to be a good mimic for the blood-brain barrier. The acceptability of the compounds to be orally bioavailable was estimated on the basis of Lipinski's rule of five (Lipinski, 2004) .

J o u r n a l P r e -p r o o f

The chemical structure of arbidol was submitted to the MolOpt webserver to develop different analogues with improved pharmacokinetic and pharmacodynamic profiles. This server suggested a total of six potential bio-isosteric replacement sites. After bio-isosteric replacement at these six sites, a total of 569 molecules were generated corresponding to these sites. These molecules were then ranked on the basis of synthetic feasibility, which led to 36 top-ranked molecules (Table 1) .

Synthetic accessibility score ranges from 1 (very easy) to 10 (very difficult) (Nath et al., 2020) .

Normally, the molecules with synthetic accessibility score of <5 are considered. To be more precise, in the current study, molecules having this score <3 were considered for further investigation. In these 36 molecules, only the core indole moiety of arbidol was kept intact while the remaining structural features were modified gradually. These 36 molecules were then undergone docking based virtual screening. A list of information on the analogues generated complementary to the six sites of arbidol is provided as supplementary data (Excel file).

To identify the multi-targeting potential of arbidol analogues against various targets of SARS-CoV-2, an exhaustive docking analysis was performed on 36 top-ranked analogues of arbidol.

All these molecules were docked against SARS-CoV-2 SP-ACE2 complex, furin, TMPRSS2 and main protease (3CLPro) and the binding affinity of their docked complexes was also calculated in terms of MM-GBSA score. The results were compared with arbidol and the molecules were ranked on the basis of their docking score, key residue interactions as well as MM-GBSA scores.

The top-ranked molecules demonstrated good docking score (G-score), displayed crucial interactions with binding site amino acid residues and shown better binding affinity (MM-GBSA) than arbidol (Table 1 and 2). The best analogue concerning each replacement site of arbidol was also identified against all the targets ( Figure 2 ). Consequently, six analogues including A_BR4, A_BR9, A_BR18, A_BR21, A_BR28 and A_BR32, identified corresponding to each site, may limit the SARS-CoV-2 SP and ACE2 interaction. These molecules manifested hydrogen bonding and hydrophobic interactions with the interface amino acid residues of SP receptor-binding domain (RBD) and ACE2, which are involved in their interaction and complex formation. The docking scores and MM-GBSA scores for these molecules lied in range of -6.13

to -4.19 kcal/mol and -50.11 to -40.12 kcal/mol respectively, which were better than the docking scores (-3.63 to -2.42 kcal/mol) and MMGBSA scores (-39.99 to -30.36 kcal/mol) shown by arbidol against ACE2 and SP.

On the other hand, A_BR5, A_BR12, A_BR18, A_BR22, A_BR28 and A_BR34 were found to be effective against priming protease furin with docking score range of -5.49 to -3.78 kcal/mol and MM-GBSA ranges from -34.86 to -22.92 kcal/mol. For another priming protease TMPRSS2, analogues A_BR2, A_BR11, A_BR17, A_BR22, A_BR28 and A_BR32 were found to show crucial interactions with docking score range -2.73 to -2.03 kcal/mol and MM-GBSA ranging from -38.36 to -27.02 kcal/mol (Table 1 ). 

Parent drug Bio-isosteric replacement 1

Bio-isosteric replacement 2

Bio-isosteric replacement 3

Bio-isosteric replacement 4

Bio-isosteric replacement 5

Bio-isosteric replacement 6

J o u r n a l P r e -p r o o f Further, the analogues which were superior to arbidol, with respect to each replacement site, were also identified for main protease 3CLPro (Figure 3) . Although arbidol did not show any significant interaction, docking score (-4.89 kcal/mol) and MM-GBSA score (-12.23 kcal/mol) with 3CLPro, surprisingly, its analogues A_BR5, A_BR9, A_BR18, A_BR20, A_BR27 and A_BR32 exhibited way better results than arbidol with docking score range -7.05 to -4.91

kcal/mol and MMGBSA score ranging from -46.94 to -33.30 kcal/mol (Table 2 ). 

It is reported that the molecules that can block the activity of ACE2 as a receptor for SARS-CoV-2 may serve as a potential therapeutic option for COVID-19 (Abdelli et al., 2020) . The 

After binding of SP to ACE2, two transmembrane proteases including furin and TMPRSS2 leads to proteolytic cleavage of SP, which facilitates the entry of the virus into the host cell, viral replication and cell-to-cell transmission (Hasan et al., 2020; South et al., 2020) . Thus, the designed arbidol analogues were docked into the binding sites of these two proteases and their 

Among all the arbidol analogues, submitted to docking based virtual screening, A_BR18 and A_BR28 displayed good results against SARS-CoV-2-ACE2 and furin, whereas, A_BR22 was found effective against furin and TMPRSS2. Therefore, these three molecules can be considered as dual inhibitors. Moreover, A_BR28 was found effective against all the three targets involved in viral attachment and membrane fusion step. At the same time, analogues A_BR5, A_BR6, A_BR9 and A_BR18 demonstrated promising results against main protease (3CLPro) that is involved in viral replication. Overall, based on in-silico results, A_BR18 and A_BR28 implied multi-targeting potential against COVID-19. The 3D view of the docked complex of these most active molecules with their respective proteins is shown in Figure 8 (A_BR18), Figure 9 (A_BR22), Figure 10 (A_BR34) and Figure 11 (A_BR28). 

The main protease (3CLPro) of SARS-CoV-2 is essential for the processing of polyproteins which are translated from viral RNA. 3CLPro acts on the Leu-Gln^Ser-Ala-Gly cleavage site of polyproteins . Since there is no reported protease in humans with the same cleavage site specificity, inhibiting this enzyme would not show any toxic effect on humans.

Therefore, the top-ranked arbidol analogues were docked within the catalytic site of 3CLPro. It is reported that the catalytic triad (His41, Cys145 and Ala285) of 3CLPro is essential for the enzymatic activity and N-terminal residue Glu166 keeps the S1 domain of this enzyme in an active conformation. Those inhibitors which show interaction with the catalytic triad and Glu166 are considered to be very good inhibitors of 3CLPro. From docking results, it was observed that J o u r n a l P r e -p r o o f arbidol and its analogues A_BR8, A_BR15 and A_BR36 did not show any interaction with the key amino acids. However, remaining analogues were found to form H-bond interactions with

Glu166. The top-ranked analogues interacted with His41, Cys145 and Glu166 while no interaction was observed with Ala285. In most of the molecules, the phenyl ring was found to interact through π-π stacking with His41. The tertiary amine group of A_BR5 

In this virtual screening process, the ADME parameters of 36 novel arbidol analogues were investigated to assess their drug-like properties. The drug-likeness was recommended for the molecules obeyed Lipinski's rule of five (mol_MW <500, QPlogPo/w <5, donorHB≤5, SASA: total solvent accessible surface area (300-1000), QPlogPo/w: Predicted octanol/water partition coefficient (-2 to 6.5), QPlogS: Predicted aqueous solubility (-6.5 to 0.5), CNS: Predicted central nervous system activity on a -2 (inactive) to +2 (active) scale, QPPCaco: Caco-2 cell permeability in nm/sec (<25 poor, >500 great), QPPMDCK: Predicted apparent MDCK cell permeability in nm/sec (<25poor, >500great), QPlogBB: brain/blood partition coefficient (-3 to 1.2), QPlogKhsa: binding to human serum albumin (-1.5 to 1.5), Percent Human-Oral Absorption: human oral absorption on 0 to 100% scale (>80% high,<25% poor). J o u r n a l P r e -p r o o f 44 A combination of scaffold morphing and a structure-based drug designing approach was successfully utilized to identify putative multi-targeting analogues of arbidol against COVID-19. Initially, the bio-isosteric replacement was done on six suggested sites of arbidol to generate a library of its analogues. From a library of 569 analogues, 36 were selected based on synthetic possibility and submitted for docking analysis against different targets of SARS-CoV-2. The binding affinity and ADME properties of these molecules were also determined. The in-silico ADME prediction conferred the drug-like properties of these analogues. The most active molecules A_BR4, A_BR9, A_BR18, A_BR22 and A_BR28 suggest plausible binding mode with the interface amino acid residues which are responsible for the interaction of spike protein with ACE2 as well as with priming proteases furin and TMPRSS2.

On the other hand, A_BR5, A_BR6, A_BR9 and A_BR18 were found effective against the main protease (3CLPro). Overall, A_BR18

and A_BR28 displayed multi-targeting potential against maximum targets considered in the study. However, further experimental validation is required to confirm their inhibitory activities against SARS-CoV-2. On the basis of these results, it can be suggested that a slight structural modification in the arbidol i.e. the replacement of tertiary amine group with primary amine and bromine with methoxy group may improve its therapeutic profile. The protocol adopted in this study may be used as a framework in the future for the development of novel multi-targeting small molecules against the COVID-19.

Huang, J., Song, W., Huang, H., Sun, Q., 2020 J o u r n a l P r e -p r o o f Predicted octanol/water partition coefficient (-2 to 6.5), QPlogS: Predicted aqueous solubility (-6.5 to 0.5), CNS: Predicted central nervous system activity on a -2 (inactive) to +2 (active) scale, QPPCaco: Caco-2 cell permeability in nm/sec (<25 poor, >500 great), QPPMDCK: Predicted apparent MDCK cell permeability in nm/sec (<25poor, >500great), QPlogBB: brain/blood partition coefficient (-3 to 1.2), QPlogKhsa: binding to human serum albumin (- 

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The authors thank Dr. Anshuman Dixit, Institute of Life Sciences (ILS), Bhubaneswar, for help and support in molecular docking analysis. S Choudhary would like to acknowledge the Indian Council of Medical Research (ICMR), New Delhi for providing SRF under sanction no: ISRM/11(61)/2017.

The Authors have no competing conflict of interest to declare.J o u r n a l P r e -p r o o f