key: cord-1000304-ps2j9eay
authors: Venkateshan, M.; Muthu, M.; Suresh, J.; Kumar, R. Ranjith
title: Azafluorene derivatives as inhibitors of SARS CoV-2 RdRp: Synthesis, physicochemical, quantum chemical, modeling and molecular docking analysis
date: 2020-06-23
journal: J Mol Struct
DOI: 10.1016/j.molstruc.2020.128741
sha: 629c2e96aca92910db20cbc06ccb26b07e8edfdf
doc_id: 1000304
cord_uid: ps2j9eay

The crystal structures of 2-(1H-indol-3-yl)-4-phenyl-5H-indeno [( Cheng et al., 2007; Lee et al., 2003) 1,21,2-b]pyridine-3-carbonitrile (Ia) and 2-(1H-indol-3-yl)-4-(4-methoxyphenyl)-5H-indeno [( Cheng et al., 2007; Lee et al., 2003) 1,21,2-b]pyridine-3-carbonitrile (Ib) were determined using single crystal X-ray diffraction. Both the compounds belong to the triclinic system with the P-1 space group. The azafluorene ring system in both the compounds is effectively planar. The intermolecular interactions present in the compounds are discussed using Hirshfeld surface analysis, QTAIM and NCI. Compound Ib formed a strong interaction (−24.174 kJ/mol) with the solvent molecule. Both the compounds were geometry optimized using DFT/B3LYP level of theory. The compound's drug-like behaviors were studied using HOMO-LUMO analysis. The homology modeling of SARS CoV-2 RdRp was done utilizing the PDB 6NUR_A as a template. The model showed above 99% similarity with its preceder SARS CoV. The molecular docking analysis of the synthesized compounds was carried out along with some suggested drugs for COVID-19 and some phytochemicals. The docking results were then analyzed. The binding free energy of the complexes were calculated using MM-PB(GB)SA and ADMET properties of Ia and Ib were also predicted. Some suggestions are given from this analysis.

Coronaviruses (CoV) in humans can cause the common cold to Severe Acute Respiratory Syndrome (SARS). At the beginning of the 21 st century, the CoV outbreak was identified in the southern part of China called SARS, spread more than 25 countries with the lethal rate of 10% [1, 2] . Next broke out of the corona was happened on 2012 in Saudi Arabia, named Middle East Respiratory Syndrome (MERS) having a fatality rate of 3.5% [3, 4] . A new public life threat was identified at the end of 2019, named as novel coronavirus -2019, and originally emerged from the city Wuhan, China [5] . The World Health Organization (WHO) announced a CoV outbreak on 30 th Janurary 2020. On Basically, there are four types of CoV's namely α, β, γ and δ were identified. Among the four γ and δ affect birds, whereas, α and β affect mammals [6] . This SARS CoV-2 is belonging to β-CoV with four proteins, namely, spike (S) protein (binds with the host cell ACE2 receptor), membrane (M) protein (act as an organizer of CoV assembly), envelope (E) protein (interacts with membrane protein to form an envelope) and nucleocapsid (N) protein (viral RNA genome replication) [7] .

Treating such CoV includes, increase the native human immune system and inhibit the replication process of CoV inside the human body. The replication process can be inhibited by targeting one of the proteins, mainly, the nucleocapsid protein. RNA dependent RNA polymerase (RdRp) is one of the enzymes, which catalyze the RNA replication and transcription process. Some nucleotide analogous drugs like Remdesivir, galidesivir target this RdRp and interrupt as a nucleotide in the process of replication. These nucleotide analogous drugs were used as an anti-viral drugs against some diseases caused by RNA viruses like Ebola, HIV and Zika virus [8] [9] [10] [11] . Anti-viral drugs such as Lopinavir and Ritonavir showed inhibitory action against SARS CoV-2 [12] . Chloroquine and Hydroxychloroquine are also suggested for the COVID-19 treatment. Chloroquine and Remdesvir showed inhibition activity against SARS CoV-2 in-vitro [13] .

Azafluorenes have attracted researchers towards its side by showing some moderate to good biological activities. The alkaloid extracted from the plant Polyalthia debilis contains 4azafluorene derivatives showed anti-microbial, anti-malarial and cytotoxic activities [14] .

Naturally obtained onychine showed anti-fungal activity against candida albicans [15] also antimicrobial activity against Staphylococcus aureus [16] . Further, these derivatives act as an adenosine A2A receptor antagonist [17] . These derivatives are effective for neurodegenerative diseases [18] by having anti-depressant property [19] . Some derivatives are reported to have Phosphodiesterease inhibitory [20] , cytotoxic [21] , anti-inflammatory [22] , anti-oxidant [23] and anti-histamine [24, 25] properties. Girgis anti-viral activities [27] . Pyridine fused with indole compounds were screened for their antitumor activities are also shown moderate to good anti-bacterial activity against Staphylococcus aureus and Pseudomonas aeroginosa [28] .

Vincristine, Vinblastine, Vinorelbine and Vindesine are vinca alkaloids used as intravenous drugs (anti-mitotic drugs) prescribed for the treatment of various types of cancer, such as, lung cancer, breast cancer, leukaemia, melanoma and lymphoma [29, 30] . These drugs bind to the β-tubulin subunit and changes the conformation of tubulin, thus they control the cell mitotic process (cell division) [31] .

The repurposing of approved drugs were already done by many research groups [32] and which are still in the trials. Therefore, this work demonstrates the synthesis, structural and packing analysis of two indole containing azafluorene derivatives. The intermolecular hydrogen bonding interactions are qualified and quantified using Hirshfeld surface analysis, QTAIM (Quantum Topological Atoms In Molecules) and NCI (Non-Covalent Interaction) analyses. Also, the homology modeling of the structure of RNA dependent RNA polymerase (RdRp) of SARS CoV-2 is discussed due to the unavailability of three dimensional PDB (Protein Data Bank) structure. Finally, the drugs to treat COVID-19 are suggested based on the results of in-silico molecular docking analysis.

Compounds C 27 H 17 N 3 (Ia) and C 28 H 19 N 3 O, C 2 H 6 OS (Ib) were synthesized using the following procedure.

A mixture of 3-(1H-indol-3-yl)-3-oxopropanenitrile (0.1 g, 0.543 mM), benzaldehyde (0.543 mM), ammonium acetate (0.1 g, 1.1 mM) and 2,3-dihydro-1H-inden-1-one (0.543 mM) was dissolved in ethanol (10 ml) and heated to reflux on a heating mantle for 2 h. After completion of the reaction as evident from TLC, the reaction mixture was set aside at ambient temperature for 6-7 h. The precipitate formed was filtered and dried to get a pure product. The crystals were obtained from the slow evaporation technique by dissolving the product in DMSO.

(Yield: 81%; m.p: 267 -268°C) (Fig. S1 ).

A mixture of 3-(1H-indol-3-yl)-3-oxopropanenitrile (0.1 g, 0.543 mM), 4methoxybenzaldehyde (0.543 mM), ammonium acetate (0.1 g, 1.1 mM) and 2,3-dihydro-1Hinden-1-one (0.543 mM) was dissolved in ethanol (10 ml) and heated to reflux on a heating mantle for 2 h. After completion of the reaction as evident from TLC, the reaction mixture was set aside at ambient temperature for 6-7 h. The precipitate formed was filtered and dried to get a pure product. The crystals were obtained from the slow evaporation technique by dissolving the product in DMSO. (Yield: 77%; m.p: 271 -272°C) (Fig. S1 ).

A good quality optically clear 0.21 x 0.2 x 0.18 mm 3 sized crystal was selected for the intensity data collection using Bruker kappa APEX II diffractometer using the MoKα radiation ( λ = 0.71073Å) source. The intensity data were collected at 20°C. Absorption correction was carried out using the SADABS program with multi-scan method. Full-matrix least-squares refinement procedure was used for solving structures using SHELXL [33] . All the non-hydrogen atoms were refined anisotropically and hydrogen atoms were positioned from the difference fourier maps and refined isotropically. Hydrogen atoms were placed in calculated positions, with C-H = 0.93-0.98 Å and N-H = 0.86 Å, and allowed to ride on their respective carrier atoms, U iso (H) = 1.2U eq (C) for CH 2 , CH and NH groups.

Initial structural solution of Ib showed co-crystallized completely disordered solvent molecule (DMSO) which was modeled and refined using PART command along with a free variable. The solvent molecule is disordered over two sets of sites in a 0.515(2):0.485(3) ratio.

The final refined structure was validated using PLATON [34] and CheckCIF routine from IuCr.

Thermal ellipsoidal image and molecular packing diagrams were generated using ORTEP [35] and Mercury [36] . CCDC 1997850 (Ia) and CCDC 1997851 (Ib) contain the supplementary crystallographic data. The data can be obtained free of charge from The Cambridge

Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures. The crystallographic data and refinement parameters were listed in Table 1 .

Theoretical DFT calculations were done using the computational package ORCA 3.0.3 [37] . To obtain optimized geometry, the input file for ORCA was generated from experimental crystal data as initial coordinates with the DFT B3LYP level of theory with 6-311G(d,p) [38] as a basis set. The frontier molecular orbital analysis was carried out using this optimized geometry.

Hirshfeld surface (HS) along with the fingerprint plot analysis has been done using the software CrystalExplorer 3.1 [39] . For the analysis of QTAIM (Quantum Theory of Atoms In Molecules) and NCI (Non-Covalent Interaction), the Single Point energy calculation was done using the single crystal X-ray geometry as the input. The output wavefunction file was used for the analysis. For QTAIM analysis Multiwfn [40] software was used and for NCI analysis, NCIPLOT [41] program was used. The outputs were combined and visualized through VMD [42] software. 

The three dimensional models of the RdRp of SARS CoV-2 were produced using the homology modeling software MODELLER 9.23 [47] . As stated earlier, the target sequence has 99.11% identical with the template; the coordinates from the template to the Structurally Variable Regions (SVR), Structurally Conserved Regions (SCR), C-termini and N-termini were allotted on the basis of the fulfillment of the spatial restraints. Ten models were produced, out of which the model having lowest energy was chosen for the next step of energy minimization. This step is essential to eliminate the geometrical errors occurred during the modeling stage. This process utilizes the software GROMACS-5.1.2 [48] . The minimization process uses Steepest descent algorithm using GROMOS96-43a1 as a force field. The modeled structure was put inside a cubic box of 8.061 nm x 8.168 nm x 8.383 nm size, containing 57,689 SPC216 water molecules. Eight sodium ions were added to neutralize the system. Physicochemical parameters that is, atomic and amino acid composition, isoelectric point, instability index, Grand Average of hydropathicity (GRAVY) were analyzed using ProtParam tool of ExPASy [49] .

The RdRp of SARS CoV-2 model is validated using PROCHECK [50] , PROVE [51] ,

ERRAT [52] , Verify 3D [53] and along with Ramachandran plot [54] . Since it is a new virus, its active sites can be predicted using some web servers. Here 3DLigandSite [55] web server (http://www.sbg.bio.imperial.ac.uk/3dligandsite/) was used to predict the binding sites.

A database containing more than 500 molecules including suggested drugs for COVID- were performed using AutoDock vina [56] in PyRx [57] software. The final results were analyzed and visualized on the basis of docking scores using Chimera [58] and PyMol [59] software's.

PharmaGIST [60] 

The binding free energy was calculated using farPPI server [65] . The input files were generated using Chimera [58] . The lowest binding energy, protein-ligand complex from the docking analysis was selected. The partial charges of the ligands were calculated using the AM1-BCC method [66] using the DockPrep tool in Chimera. The force fields, GAFF2 [67] and ff14SB [68] were used for ligand and protein respectively.

The two compounds differ by the substituent at fourth position of azafluorene ring. This substitution does not affect the crystal system. The ORTEP diagrams with thermal ellipsoids at 30% probability with an atom numbering scheme for Ia and Ib are shown in Fig. 1 and 2 .

In both the compounds, the azafluorene ring is essentially planar with the deviation of 0.0198 (2) Fig. 4) . (Fig. S2 ). This interaction is colour coded as blue in NCI index indicating strong interactions (Fig. S4) . The energy of this interaction from QTAIM descriptors is found to be -14.856 kJ/mol. The 'sign( )ρ' value is -0.0177 a.u. 

The studies on frontier molecular orbital reveal the chemical reactivity, chemical hardness or softness of the molecule and kinetic stability [81] . All the calculated energy parameters along with a partition coefficient (log P) and dipole moment are given in Table 7 . It can be seen from Fig. 5 that the HOMO orbitals are located on both cyanopyridine and indole moieties while LUMO orbitals are located on azafluorene ring, nitrile group and substituted aryl rings. From the molecular orbital analysis, the substitution has an influence on the electron accepting ability of the compounds. The intra-molecular charge transfer interactions of both the compounds are nearly the same as evidenced from their energy gaps. The compound Ia is more reactive than Ib. This is evident from low chemical hardness (η) and high softness (S) for Ia than in Ib. Based on the values of electronegativity (χ) and chemical potential (µ) Ia has more electron attracting ability than Ib and this is supplemented by a high electrophilicity index (ω) of Ia. The cell membrane permeability of Ib is higher than Ia 

The best model given by the PharmaGIST revealed four pharmacophric features includes two hydrogen bonding acceptors and two aromatic rings (Fig. 6) . Further, the Drug-likeliness properties like physicochemical properties, lipophilicity, pharmacokinetics and toxicity were predicted for compounds Ia and Ib and given in Table. 8. Both the compounds do not violate the Lipinski's rule of 5 [83] inferred from the physico-chemical and lipophilicity properties. Both the compounds do not show mutagenicity, tumorigenicity, irritating and reproductive effects. Also, these compounds have no Blood-Brain Barrier permeation ability. However, these compounds have CYP450 inhibition effects except CYP3A4 and 2D6. 

The final minimized potential energy of RdRp model is -418539 kJ/mol. The root mean square deviation between the template (6NUR_A) and model is 0.0016Å. The superimposed

figure of template and model is shown in Fig. S6 . The final protein model contains thirty six αhelices, fifteen β-strands and fifty one coils (Fig. 7) . 

The novel corona virus is a beta-corona virus having single positive strand RNA [84] .

The multiplication/replication and transcription from an RNA template of this virus is facilitated by multi-subunit non-structural proteins (nsp7, 8 & 12) . The co-factors nsp7 and 8 accelerates nsp12, which is a core catalytic unit of the RdRp, increases the activity of template binding and processing [85] . The study around the structural features of RdRp is a key to design a drug that can interact with this protein and hence to suppress its activity of replication. This nsp12 resembles a cupped "right hand" structure having fingers domain (amino acids (a.a) 180-465 & 512-564), a palm domain (a.a 466-511 & 565-699) and a thumb domain (a.a 700-803) (Fig. S8 ) [46] . The enzymatic activity of this polymerase is highly dependent on the conserved active site SER643-ASP644-ASP645 residues located at the palm domain [85] . The residues in the finger domain LYS429 and ARG439 arrange the incoming NTP (Nucleotide Tri Phosphate) in a perfect manner and provide a gateway to the catalytic center and LYS384 and SER385 arrange themselves to hold the template RNA strand [86] . At the catalytic center, the base of the NTP binds with the template though the 2' and 3' hydroxyl groups form hydrogen bonds with the residues THR564, ASN575 and ASP507. Also, VAL441 stacks the +1 template RNA base to support the base pairing of NTP's [46] . Therefore, targeting the above mentioned residues may greatly affect the catalytic activity and processivity of the RdRp. The docked poses of compounds Ia and Ib are shown in Fig. 9 . (Table S2) . Moreover, Ritonvir (-8.3 kcal/mol) can bind tightly with the polymerase and interact with one of the catalytic residues ASP644 (Table S2) . Therefore, these drugs can directly interfere with the enzymatic activity, thus preventing the replication. The similar interaction is observed in some vinca alkaloids like, vindesine (-8.7 kcal/mol), vincathine (-7.9 kcal/mol), vincristine (-7.8 kcal/mol), vinblastine (-7.2 kcal/mol) and vindoline (-6.8 kcal/mol) ( Table S3) .

The modeled compounds M-1 and M-3 have interactions with ASP644 and ASP645 (Table S4) .

Thus, these compounds may control the catalytic activity.

Galidesivir (-7.6 kcal/mol), Hydroxychloroquine (-6.3 kcal/mol), and Favipiravir (-5.8 kcal/mol), make one or more hydrogen bonds with 2' and 3' hydroxyl group of NTP interacting residues, thus obstructing the incoming NTP (Table S2 ). The similar behavior is observed in compound Ib having the binding energy of -7.8 kcal/mol (Table 9 ; Fig. 10 ) 

The proper orientation of NTP is maintained by the residues LYS429 and ARG439.

Compound Ia interacts with the residues that are nearby the above mentioned residues (Table 9 ; Fig. 10 ). Therefore, this compound may block the space for the NTP molecules to stay. The binding energy and binding free energy of this complex is -8.3 kcal/mol and -11.04 kcal/mol respectively. The decrease in binding free energy of Ia is may be due to the comparatively weak interactions with the residues as that of Ib. Vincathine (-7.9 kcal/mol), quercetin (-7.8 kcal/mol) and vincaleukoblastine (-7.3 kcal/mol) also exhibits the same interactions.

In this work, two azafluorene derivatives having different substituents at fourth position were synthesized and structural parameters were analyzed using SXRD. The change in substituent brought changes in physicochemical properties. The intermolecular interactions were analyzed qualitatively and quantitatively using Hirshfeld surface analysis, QTAIM and NCI index. The results suggest that, compound Ib forms strong interaction (-24.174 kJ/mol) with the solvent. Both the compounds were geometry optimized using DFT/B3LYP methods and its frontier molecular orbital analysis was done. The energy gap and other properties related to molecular interacting abilities were predicted. From docking analysis, the drugs, Lopinavir, Favipiravir, Galidesivir, Hydroxychloroquine and Ritonavir may be used against COVID-19.

The mentioned phytochemicals showed good binding affinities with the target indicating its potential efficacy. The compounds Ia, Ib and modeled derivatives (M-1 and M-3) interact with the RdRp indicating its potential activity. However, further in-vitro and in-vivo analyses around these mentioned compounds are required to ascertain these suggestions.

Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection

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Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group

Emerging threats from zoonotic coronaviruses-from SARS and MERS to 2019-nCoV

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status

Revisiting the dangers of the coronavirus in the ophthalmology practice Eye

Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir

The design of drugs for HIV and HCV

Purification of Zika virus RNA-dependent RNA polymerase and its use to identify small-molecule Zika inhibitors

RNA-Dependent RNA Polymerases and Their Emerging Roles in Antiviral Therapy

Drug treatment options for the 2019-new coronavirus (2019-nCoV)

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Bioactive azafluorenone alkaloids from Polyalthia debilis (Pierre) Finet & Gagnep

Anticandidal activity of eupolauridine and onychine, alkaloids from Cleistopholis patens

Synthesis of azafluorenone antimicrobial agents

Molecular analysis of hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants

Synthesis, cytotoxicity, QSAR, and intercalation study of new diindenopyridine derivatives

Onychine, an alkaloid from Onychopetalum amazonicum

2-Fluoro-4-pyridinylmethyl analogues of linopirdine as orally active acetylcholine release-enhancing agents with good efficacy and duration of action

Using the Pummerer cyclization deprotonation-cycloaddition cascade of imidosulfoxides for alkaloid synthesis

Molecular structure studies of novel bronchodilatory-active 4-azafluorenes

Synthesis, bioassay, and QSAR study of bronchodilatory active 4H-pyrano[3,2-c]pyridine-3-carbonitriles

Synthesis and X-ray Studies of Novel Azaphenanthrenes

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Combating Devastating COVID -19 by Drug Repurposing

silico studies on therapeutic agents for COVID-19: Drug repurposing approach

Drug repurposing against COVID-19: focus on anticancer agents

Rapid repurposing of drugs for COVID-19

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Structure validation in chemical crystallography

ORTEP-3 for Windows -a version of ORTEP-III with a Graphical User Interface (GUI)

Mercury CSD 2.0 -new features for the visualization and investigation of crystal structures

The ORCA program system Wiley Interdiscip

Self-consistent molecular orbital methods 25. Supplementary functions for Gaussian basis sets

MULTIWFN: A Multifunctional wavefunction analyzer

NCIPLOT: A Program for Plotting Non covalent Interaction Regions

VMD: Visual molecular dynamics

Synthesis, physicochemical and quantum chemical studies on a new organic NLO crystal: Cinnamoylproline

Basic local alignment search tool

Gapped BLAST and PSI-BLAST: a new generation of protein database search programs

Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors

Comparative protein modelling by satisfaction of spatial restraints

GROMACS: A message-passing parallel molecular dynamics implementation

ExPASy: The proteomics server for in-depth protein knowledge and analysis

AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR

Deviations from Standard Atomic Volumes as a Quality Measure for Protein Crystal Structures

Errors in protein structures

VERIFY3D: assessment of protein models with three-dimensional profiles

Stereochemistry of polypeptide chain configurations

Sternberg, 3DLigandSite: predicting ligand-binding sites using similar structures

AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading

Small-molecule library screening by docking with PyRx

UCSF Chimera -A Visualization System for Exploratory Research and Analysis

The PyMOL molecular graphics system

PharmaGist: a webserver for ligand-based pharmacophore detection

SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules

admetSAR 2.0: web-service for prediction and optimization of chemical ADMET properties

Organic Chemistry Portal

farPPI: a webserver for accurate prediction of protein-ligand binding structures for small-molecule PPI inhibitors by MM/PB(GB)SA methods

Fast, efficient generation of high-quality atomic Charges. AM1-BCC model: I. Method

Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB

Development and testing of a general amber force field

Addition of oxime derivatives to alkynyl fischer carbine complexes

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4-(4-Bromo-phen-yl)-6-(1H-indol-3-yl)-2,2′-bi-pyridine-5-carbo-nitrile

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Highlights: • Two azafluorene derivatives were synthesized and elucidated using SXRD

• Intermolecular interactions were analyzed using Hirshfeld surface, QTAIM and NCI

Compound Ib formed a strong interaction (-24.174 kJ/mol) with the solvent molecule

Both the compounds were (DFT/B3LYP) geometry optimized. Drug-like behaviours were studied using frontier molecular orbital analysis

RdRp was modeled using homology modeling technique and docking studies were performed for approved drugs, synthesized compounds and some phytochemicals

JS and MV thank the management of The Madura College for their encouragement and support.

The authors declare no conflict of interest