INTRODUCTION:

Numerous legislature of the Coronaviridae folks mingle in the human population along with characteristically stimulate reasonable respiratory infirmity¹. In contrast, Respiratory Syndrome (SARS) caused through the novel corona virus SARS-CoV as well as bird flu caused via avian influenza (H5N1) virus have emerged as two vital infectious diseases amid pandemic latent. Both infections crossed the species obstacle to infect humans. .Quinazoline compounds stand for one of the majority active classes of molecules possessing a broad spectrum of biological activity².

Corona viruses (CoVs) are single-stranded RNA viruses with enormous, enveloped along with positive wits which could infect both animals and also humans³. SARS was begin in Guangdong prefecture China at 2002 also its ultimate universal extended⁴. Chinese talisman bats proceed as SARS-CoV group hosts⁵. Intermediately hosts like civet cats also raccoon puppies, regularly marketed as foodstuff outlet in Chinese soaking markets, and enabled human diffusion⁶.

In this occasion, no innovative antiviral or accredited vaccination are accessible towards oppose SARS, even though established precautionary ladder, together with voyage bans even if patient remoteness ,in due course stopped up the SARS epidemic in 2002 and 2003. An early eruption pandemic was associated to seafood core, probably occupied into animal disclosure. In the end human-to-human illness emerged along with the along nowadays-called corona virus ailment 19 (COVID-19) dispersed exponentially at China. A distinctive corona virus, SARS-corona virus 2 (SARS-CoV-2), intimately related to SARS CoV was originate in clinics also be assumed toward survive the budding lung disease’s etiologic agent⁷. Infections are as well recognized at 24 non-china nations, interrelated through foreign trek whether sequencing correlations amongst SARS CoV-2 as well as SAR CoV. Translate keen on allied biological properties. Specifically occurrence opportunity exist presently uncertain⁸. Virus doorway into cells be synchronized through spike (S) Glycoprotein: Spike 1(S1) by spike (S) glycoprotein; spike 1 (S1) façade part helps the virus to be associated in the direction of cellular proteins. Cellular proteases hew the S Protein in the S1/S2 also S20 positions towards permit viral element access. The viral capside is next merged among the cellular membrane subunit S2-guided course⁹. It was reputable so as to angiotensin-converting enzyme 2 (ACE2) mediates SARS CoV entry as well as that serine protease TMPRSS2 which is accountable for S Protein cleavage¹⁰. Investigation of receptor requisite motif (RBM) sequences inside the receptor binding province reveal that its answerable for binding towards ACE2 also that residues encompass be conserved with SARS Co V and also SARS-Co V 2, representing to facilitate binding to ACE2 might be alike even as the similar residues be absent in other corona viruses^11,12. Some of the human ACE2 antibodies avoided SARS-CoV,SARS-CoV-2 infections¹³. Furthermore proteases are sole of the crucial also best studied proteins in corona viruses¹⁴. Its most important for the giving out poly proteins which are translated among viral RNA¹⁵. Inhibition of this viral Protease willpower outcome interested in the blocking of viral interested reproduction. SARS-and MERS-CoVs genomes comprise two open impression frames ORF1a and ORF1b translated towards two particular viral polyproteins pp1a and pp1a by host ribosome. ORF1a encodes two cysteine proteases, a papain-like protease (PLpro) and a 3CL-like protease (3CLPro). Whereas PLpro cuts the initial three cleavage sites of its polyproteins, 3CLpro is liable for cleavage of the lasting 11 locations resulting in release of a total of 16 non-structural proteins (nsp) in both SARS-and MERS-CoVs.the homodimeric form of 3CLpros is active in the presence of substrates. The crystal structures of both 3CLpros showed so as to each monomer is composed of three structural domains: domains I and II form a chymotrypsin-like structural design with a catalytic cysteine and are connected to a third C-Terminal domain via a long loop¹⁶ In the proteolytic site, all 3CL pros prefer glutamine at P1 position and leucine, basic residues, small hydrophobic residues at P2, P3 and P4 Positions, correspondingly. At P10 and P20 positions, small residues are required nevertheless; P30 Position shows no strong preference. Ever since the auto cleavage process is central for viral propagation, 3CLpro is a good drug target for anti-corona viral infection¹⁷.

In these conditions, the expansion of inhibitors towards the SRAS Co-V 2 main Protease gains significance into the drug innovation progression against COVID-19. Lately, the crystal structure of inhibitor barrier SARS-CoV 2 main protease^18,19. Presently, the Insilico study includes develop into a preliminary also crucial part of the drug innovative process, as well as which influence the whole course of drug design and progress. This is typically given that in silico offer momentous cost, effort and time reductions as well as more green another compared to synthetic chemistry. Lastly the mainly imperative reflection with in silico move towards be with the purpose of its spare investigational animals. Moreover, for generating particular inhibitors, awareness of the differences between infective organisms as well their relevant host’s biochemical pathways, metabolism and also macromolecular structure, metabolism, in addition to detailed description of target proteins and macromolecules being a primary consequence²⁰.

MATERIALS AND METHODS:

Computational resources Molecular docking simulations were used to predict the correct binding conformation of the ligand in the enzyme-binding pocket. The scoring function (dock score) comprised steric and electrostatic components of binding parameterized universal force fields. This utility allowed screening a set of compounds for lead optimization. Molecular graphics laboratory (MGL) tools and Auto Dock vina PyRx virtual screening tool was downloaded from www.scripps.edu, ChemSketch was downloaded from www.acdlabs.com, biovia Discovery studio visualizer was downloaded from https://www.3dsbiovia.com/biovia-discovery. The Mol file of Ligand to PDB format translation was carried out by using Chem 3D Pro 8.0 and protein to PDB format translation was carried out carried out by Molecular operating environment (MOE) were used. Molecular docking carried out by using a dell Personal Computer (PC) with a intelcore processor and Windows 7 operating system. Docking studies were carried out using the Ligand docking methology (GRIP) batch docking method implemented in auto dock 4 software packages.

Molecular Docking Studies:

Grounding of Macromolecules:

Main Protease and spike Protein domain complexed with ACE2 (PDP ID: 6M2N, 6VW1) of the crystal l structures be retrieved in the RCSB PDB (Protein data Bank) catalog. The graphical client boundary series “Auto dock utensils be used to set up, scuttle and also scrutinize the docking study results. Since, ligands exist not peptides, Gasteiger indict be structured followed with non polar hydrogen’ was combined .Auto dock desires for pre designed grid maps, sole for ultimate atom appearance in attendance into the ligand mortal docked keen on the same time as it provisions the potential energy arise. The grid requirements enclose the location of magnitude that is active site in the macromolecule.

Ground work of Ligands, Investigation of Drug Likeness:

The structure forms of the subsequent the 3D structure crystal forms of the subsequent energetic molecules of Quinazolin-4-one were designed zone of ChemDraw zone database, drug-likeness of ligands texture are calculated for the preferred active compounds active by pkCSM software.

Legalization of target protein- ligands structures:

Auto dock 4.0 Tactic be validated with the relevant co-crystallized ligands of target proteins to make sure the effective selection process. Auto dock 4.0 represents realistic RMSD attain and precise requisite with target receptor. In this research, for SARS CoV II Protein (PDB ID: 6M2N, 6VW1), the energetic location were determined in the Biovia Drug discovery studio visualizer.

Docking:

Docking was performed using PyRx auto dock vina. The results were quantified in terms of free binding energy. The highest binding energy values corresponding to the RMSD value of zero were considered as the binding affinity value of the Ligands. The [post dock analysis was made using biovia discovery studio visualizer. The prepared crystal structures of ligand and active site of various enzymes such as crystal structure of [PDB ID: 6M2N] were subjected to Auto dock Vina for measuring the binding energies. The docking grid box was set at approx. above 90 90 90 and genetic algorithm (GA) with default settings was employed for the studies. In the search parameter, number of runs and the other settings were left as default. The results of docking calculations seen in the output were in word format²¹.

The position and orientation of Ligands in protein receptor and the interaction with amino acids that bound to the ligand were analyzed and visualized with Auto Dock tools. During the docking process the top ten conformations were simulated for each of the compound after the minimization of the energy. The binding energy of each ligand against 3CL PRO macromolecule was predicted using auto dock vina, which is one of the most commonly used docking software. in the docking procedure ,eight binding pose were obtained, and the binding bose with the highest binding energy corresponding to the RMSD value of zero was considered as the binding affinity of the ligand. The amino acid residues interacting with the selected quinazolinone derivatives and all molecules showed hydrogen bond interactions, many having Vander walls attraction with different amino acid residues in the binding site. In general, all the libraries of quinazolinones were found to have more binding affinity than the chloroquine. This is due to an increased number of hydrogen bond, vanderwalls attraction with the amino acids of the binding site. The most active compound was which showed hydrogen bond interactions over the enzyme although pialkyl interactions, also pi-sigma interactions were analyzed.

Drug likeness, Bio activity prediction, and ADMET properties:

The molecular structure were drawn by using advanced chemistry department (ACD)/ChemSketch version 12.0 as well as (SMILES) Simplified molecular –input line entry system notation data be created and fed keen on these software’s to calculate the parameters. In silico studies which have helped to resolve the activity of the compound while within the body while as well acting as a vital tool for the drug innovative process also for the lead optimization. The molecular descriptors, drug likeness features of 2 substituted pyrazolone fused quinazolin-4-one derivatives done by using the molinspiration tool server (http://www.molinspiration.com) which given the outcome of Lipinski’s rule of five (RO5). ADMET of the ligands is pharmacokinetic property computation to facilitate, be necessary toward exist examined to launch their utility inside the body. The ADMET legacy of the ligands was deliberate, making use of admetSAR (http://lmmd.ecust.edu.cn/admetsar2/²².

RESULTS AND DISCUSSION:

Designing:

The sequence of molecules were designed depends on the outcome present in the literature associated towards the active binding site of SARS Co-V 2.the structural features for efficient interaction with the receptor as well as various parameters that have been explored in this study. The prominent features known from the literature were H- Bonding and π-stacking interactions are crucial, essential for the binding of inhibitors within the active position of SARS CoV 2. The amino acid residues interacting within the newly designed quinazolin-4-one derivatives and also except few all the compounds exibits hydrogen bond interactions, many having Vander walls attraction among different amino acid residues in the binding site. In general, all the selected quinazolinones were found to have excellent binding affinity because of an increased number of hydrogen bond, vanderwalls attraction with the amino acids of the binding location. The most active moiety was which exhibited hydrogen bond interactions over the enzyme although pialkyl interactions, also pi-sigma interactions were analysis (QPZ1-QPZ5) listed in Table:2

Molecular docking studies:

In order to categorize the potential aspirant for managing COVID-19, molecular docking done as well executed newly designed synthetic molecules from the derivatives of quinazolin-4-one on the binding pocket of enzyme COVID-19 (PDB ID:6M2N,6VW1). Assortment of lirature which was undoubtedly says that entry of virus within the host cell by the assistance of ACE2 receptors-Protein binds in a straight line to the Angiotensin Converting Enzyme 2 (ACE2) receptor of the human host cell face so as to enable the virus access and replication. In this study selected PDP ID: 6VW1 where spike protein its complexed with ACE2 towards explore the binding affinity of quinazolin-4-one derivatives with the complex²³. all these designed compounds (QPZ1-QPZ5) were docked in opposition to the target protein COVID 19 as well as ranked depends on their docked value. Generally, Compounds exhibiting docked score of 7.0 or even less or more than that are thought concerning the better agent for restraint of the COVID-19.A complete assessment could be done and enlisted in the table no: 2 and the table exemplify the list of active compounds acquired later on docking studies. Those active as well designed molecules possess excellent docked value of more than 7.0 kcal/mol. Among 5(QPZ1-QPZ5) compounds were selected depends on the binding affinity with 6M2N AND 6VW1 (fig: 1-3).from designed proposed molecules, Quinazolin-4-one derivatives QPZ5 having the best docked value (-9.5kcal/mol) with SARS-CoV2 Main Proteases (6M2N) and also QPZ2 possess the best docked value of (-8.6kcal/mol) with SARS CoV2 Spike Protein (6VW1).

Molecular Interaction Studies:

Drug likeliness, Bio activity and ADMET evaluation:

In drug development, Absorption, distribution, metabolism, and elimination (ADME) properties play a vital role in the victory or stoppage of aspirant molecules .reduced properties could limit the exposure of the molecules to the target enzyme. Toxicity is one more especially imperative factor which regularly overshadows the ADME actions. Lipinski’s rule is functional in assess the bioavailability of the orally administered drugs. The newly designed molecules were studied for the drug likeness of molecular properties as well as bioactivity by molinspiration. further the prediction of ADMET Properties was used admetSAR databases. All the newly designed compounds in order to veber’s rule which they have rotatable bonds less than 10 as well TPSA not more than 140.and also its indicate that designed compounds may have good oral absorption²⁴. Table 1 represents that all the new quinazolin-4-one of drug likeness properties. Human Intestinal Absorption value should be in the 0.9 and further which indicates good intestinal absorption. AMES toxicity test evaluation employed to find the whether a drug is mutagenic or not so as all the designed compounds (QPZ1-QPZ5) which is influenced negative values, that is they are non-mutagenic as well as non carcinogenic and also designed compounds have exhibited lower oral acute toxicity LD50 which is a dose that causes of 50% test population .and also was found to be somewhat higher range, could be measured to be safe as well as range of LD50 listed in table-3. The bioactivity value of the designed quinazolin-4-one derivatives as G-Protein coupled receptor(GPCR) ligand, nuclear receptor ligand, ion channel modulator, a kinase inhibitor, protease inhibitor, also enzyme inhibitor were analyzed as well represented in table-4.A Moiety exhibited bioactivity value of more than 0.00 is most expected to reveal significant biological activity. Bioactivity scores be additional towards 0.0 for enzyme inhibition when compared to other mechanisms²⁵. Compounds had bioactivity value more than 0.00 for enzyme inhibition, therefore which could be they can be measured to possess significant biological activity by the respective mechanism. The newly designed compounds given bioactivity score between -0.21and -0.14. These results validate the basis at the back of designing series as SARS CoV2 inhibitor.

Quinazoli-4-one

Mpro (6M2N) Spike Protein (6VW1)

Figure 1: General Structure of newly Designed Compounds and 3D crystal structure of the Macromolecules of COVID-19

Table1. Physicochemical effects of the energetic molecules among the rules of drug-likeness

*Ligands*	MW	*Logp*	*Alogp*	*HBA*	*HBD*	*TPSA*	*Nrb*	*No of violation*
QPZ1	457.94	4.12	4.33	4	3	77.69	5	0
QPZ2	468.49	3.37	3.58	6	3	123.52	6	0
QPZ3	453.52	3.47	3.68	5	3	86.93	6
QPZ4	466.57	3.53	3.74	5	3	80.93	6	0
QPZ5	441.49	3.60	3.81	4	3	77.69	5	0

Table2. Interactions of COVID-19 Mpro (6M2N) and Spike Protein (6VW1) amino acid residues with Quinazolin-4-one moieties on receptor sites

Code	Binding affinity Kcal/mol		Vander Waals		H.bond		Pi –alkyl		Pi-sigma
Code	6M2N	6VW1	6M2N	6VW1	6M2N	6VW1	6M2N	6VW1	6M2N	6VW1
QPZ1	-9.0	-8.3	THR D:24,26,45,SER D:46,123, LEU D:27,141, ASN D:119,GLY D:143,THR D:26	GLU A:536,B:435,GLN A:531,ASN A:586,B:432,GLU A:527,536,B:435,PRO B:538,HIS B: 540	ASN D:142	HIS A:535	----	LEU A:539,PRO B:590	THR D:25,TYR D:118(pi-pi stacked	LYS A:534,B:541(Pi cation)
QPZ2	-9.2	-8.6	CYS D:44,SER D:46,123,ARG B:298,LEU D:141,ASN D:142,GLY D:143,MED T:49,THR D:45	PRO B:135,612,THR B:158,613,ASN A:134,159,GLU A:160	ASN D:119	----	----	LEU B:162,TRP B:163	THR D:25,TYR D:118(pi-pi stacked)	TYR B:255
)QPZ3	-9.0	-8.3	ILE A:106,200,THR A:111,292,VAL A:202,SER A:158,ASP A:153,295,PHE A:8,PRO A:108,GLY A:109,GLU A:240	PRO B:135,612,TYR B:158,613,ASN B:134,159,GLU B:160.	PHE A:294,GLN A:110	----	ILE A:249,ASN A:151(pi-pi T shaped)	LEU B:162, TRP B:163(pi-pi T shaped)	HIS A:246(pi cation)	TYR B:255
QPZ4	-8.8	-8.3	PRO A:108,293,VAL A:104,202,ILE A:106,200,THR A:111,292,SER A:158,ASN A:151,ASP A:295,PHE A:8,GLY A:109,GLU A:240	GLU A:527,536,B:430,435,ASN B:432,HIS B:540,PRO B:538,ILE B:436	GLN A:110	HIS A:535,GLY A:537,GLN A:531	ILE A:249	LEU A:539,PRO B:590	HIS A:546(pi cation)	LYS A:534,B:541(PI cation)
QPZ5	-9.5	-8.2	LEU D:27,141,VAL D:42,THR D:26,45,HIS D:41,GLY D:143,ARG D:298,SER D:123	LYS A:534,GLU B:430,435,527,536,HIS A:535,B:540,ASN A:586,B:432,PRO B:538,590	CYS D:44,SER D:46,ASV D:119,142	GLN A:531,GLY A:537	TYR D:118,D:3WL401	LEU A:539	THR D:25	LYS A:541(pi cation)

Table3. ADMET possessions of newly designed Quinazolin-4-one derivatives

Ligands	HIA	BBB	AMES Toxicity	Carcinogenicity	LD 50 in rat(mol/kg)
QPZ1	0.9045	0.9802	Non -toxic	Non-carcinogenic	2.066
QPZ2	0.9592	0.9762	Non-toxic	Non-carcinogenic	2.156
QPZ3	0.9013	0.9771	Non-toxic	Non-carcinogenic	2.552
QPZ4	0.8834	0.9803	Non-toxic	Non-carcinogenic	2.056
QPZ5	0.8920	0.9802	Non-toxic	Non-carcinogenic	2.085

Table: 4.Bioactivity score of proposed molecule of Quinazolin-4-one derivatives

C.Code	GPCR Ligand	Ion channel modulator	Kinase inhibitor	Nuclear receptor ligand	Protease inhibitor	Enzyme inhibitor
QPZ1	0.12	0.34	0.47	0.16	0.12	0.18
QPZ2	0.21	0.39	0.54	0.20	0.18	0.21
QPZ3	0.14	0.39	0.47	0.15	0.13	0.18
QPZ4	0.10	0.36	0.41	0.12	0.10	0.14
QPZ5	0.11	0.35	0.43	0.13	0.11	0.16

HIA: human intestinal absorption; BBB: Blood-Brain Barrier; LD50: Lethal Dose, 50%

QPZ5 (6M2N) QPZ2 (6VW1) QPZ5 (6VW1) QPZ2 (6M2N )

QPZ5 (6M2N) QPZ2 (6VW1) QPZ5 (6VW1) QPZ2 (6M2N)

Figure 2: Best Binding pose and 2D Structure of the molecular intention with Main Protease and Spike Protein (6M2N, 6VW1)

From above study the docking poses was produced according towards docking parameters and their resultant binding pockets. These investigations be supposed helpful for considerate the binding interactions over the targeted protein. Molecular docking studies of selected quinazolin-4-one derivatives be take away and in addition docked binding affinity values of selected derivatives resulting within the value of -8.2kcal/mol and -9.5kcal/mol which listed at table -2 and Fig.2 . Each and every one of the proposed molecules be set up towards effectively clutch behind the SARS CoV 2 Mpro and Spike protein as a outcome of entirely the capable site into intend protein. The result of docking exploration be exhibited to every one of the docked moieties include lower energy value (high binding energy value). Moreover the various interaction value of designed molecules (QPZ1-QPZ5) which showed at table-2. Exemplify the most excellent low binding energy (high binding energy values) for the docked compounds. Along with 5 Ligands so as to be docked by the enzyme Mpro and spike protein the substituted NO2 and F group with novel Quinazolinone of ligand (QPZ2 and QPZ5) showed the majority effective in the midst of high binding score of -8.6kcal/mol and -9.5kcal/mol The substituted ligand Cl, OCH3 group exibits best docked score of (QPZ1–QPZ3 ) 8.3kcal/mol and 9.0kcal/mol and Substituted ligand N(CH3)2 (QPZ4) molecule exibits score of - kcal/mol while the ligand 30E -6.0 kcal/mol with 97.97 value of TPSA based 808kcal/mol and -8.3kcal/mol. Among all the selected ligands no violation exibits drug likeness properties. Further among entire selected quinazolinone molecules left over the molecules bare admirable blood brain barrier (B.B.B), human intestinal absorption (HIA), with no carcinogenicity and AMES negative as well as good bioavailability. The docked ligand configuration display Hydrogen bond and electrostatic interaction, Pi alkyl and Pi sigma interactions present in table-2.These communications showing that Ligands bind profound in the core of energetic site where the quinazoli-4-one ligand binds against action of SARS-CoV2 Enzymes.

CONCLUSION:

In present research, include and selected molecules of quinazoli-4-one derivatives followed by explore Sars CoV2 Mpro and Spike Protein Enzymes binding interaction by docking study using PDB ID: 6M2Nand 6VW1 . A number of proposed quinazolinone synthetic molecules in that some of moieties which produce with a excellent range of binding score were confirmed. Molecular docking studies data given that the most potent with the high docking score -9.5kcal/mol and 8.6kcal/mol as well as ADMET belongings. Based on the docking scores and physiochemical properties of the compound were selected and additional studies furthermore this study suggests in the purpose of the selected Compounds build known the imperative action against main protease and spike protein enzyme which may be useful to develop better inhibitory Sars CoV 2 of quinazolin-4-one derivatives and also sets necessitate for further series of molecules will be synthesized and tested for SARS CoV 2 activity.

ACKNOWLEDGEMENT:

The authors are very much gratified to Annamalai University, Annamalai Nagar, Chidambaram, Tamilnadu, India, for the supervision for successful academic philosophy research.

The authors are also thankful to the Principal and Management of Karpagam College of Pharmacy, Coimbatore, for providing necessary infrastructure.

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Received on 30.11.2020 Modified on 13.06.2021

Research J. Pharm. and Tech 2023; 16(5):2470-2476.

DOI: 10.52711/0974-360X.2023.00407