key: cord-0829136-fhfvbn8n
authors: Hasan, Mahmudul; Parvez, Md. Sorwer Alam; Azim, Kazi Faizul; Imran, Md. Abdus Shukur; Raihan, Topu; Gulshan, Airin; Muhit, Samuel; Akhand, Rubaiat Nazneen; Ahmed, Syed Sayeem Uddin; Uddin, Md Bashir
title: Main Protease Inhibitors and Drug Surface Hotspots for the Treatment of COVID-19: A Drug Repurposing and Molecular Docking Approach
date: 2021-05-18
journal: Biomed Pharmacother
DOI: 10.1016/j.biopha.2021.111742
sha: 185d0f07b384b8f081e78fd4e82898d7f61b8f2f
doc_id: 829136
cord_uid: fhfvbn8n

Here, drug repurposing and molecular docking were employed to screen approved MPP inhibitors and their derivatives to suggest a specific therapeutic agent for the treatment of COVID-19. The approved MPP inhibitors against HIV and HCV were prioritized, while RNA dependent RNA Polymerase (RdRp) inhibitor remdesivir including Favipiravir, alpha-ketoamide were studied as control groups. The target drug surface hotspot was also investigated through the molecular docking technique. Molecular dynamics was performed to determine the binding stability of docked complexes. Absorption, distribution, metabolism, and excretion analysis was conducted to understand the pharmacokinetics and drug-likeness of the screened MPP inhibitors. The results of the study revealed that Paritaprevir (-10.9 kcal/mol) and its analog (CID 131982844) (-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitors compared in this study, including remdesivir, Favipiravir, and alpha-ketoamide. A comparative study among the screened putative MPP inhibitors revealed that the amino acids T25, T26, H41, M49, L141, N142, G143, C145, H164, M165, E166, D187, R188, and Q189 are at potentially critical positions for being surface hotspots in the MPP of SARS-CoV-2. The top 5 predicted drugs (Paritaprevir, Glecaprevir, Nelfinavir, and Lopinavir) and the topmost analog showed conformational stability in the active site of the SARS-CoV-2 MP protein. The study also suggested that Paritaprevir and its analog (CID 131982844) might be effective against SARS-CoV-2. The current findings are limited to in silico analysis and lack in vivo efficacy testing; thus, we strongly recommend a quick assessment of Paritaprevir and its analog (CID 131982844) in a clinical trial.

COVID-19 is a rapidly spreading viral infectious disease caused by a beta coronavirusthe novel coronavirus SARS-CoV-2. The infection was first described in China in late December 2019, and within three months, 202 countries, territories, and conveyances had reported COVID-19 cases within their boundaries [1, 2] . This emerging human pathogen is causing acute respiratory tract infection with significant morbidity, need intensive care facilities and case fatality is most common. Even the organized health systems of many countries are also facing J o u r n a l P r e -p r o o f greatest difficulties to tackle COVID-19. Without delay, COVID-19 has become a global public health emergency and been declared a pandemic by the World Health Organization & this outbreak poses a huge threat to humans [3] .

SARS-CoV-2 (also called 2019-nCoV) is a enveloped, single-stranded, positive-sense RNA virus with genome sizes ranging from 26-32 kb and virion sizes from 50-200 nanometers in diameter [4] . In addition, zoonotic virus SARS-CoV-2 is distantly related to MERS-CoV and SARS-CoV (80.26%), but exhibits dissimilarities that may influence the process of pathogenesis [5, 6, 7] . SARS-CoV-1 and MERS-CoV mainly affect people via nosocomial spread, while this variant of human coronavirus frequently spreads through community transmission [8] . In addition, it infects through the same entry point, the angiotensin-converting enzyme 2 (ACE2) receptor, studies have confirmed a higher affinity of SARS-CoV-2 to human ACE2 than that of previous CoV strains and does not use other receptors such as dipeptidyl peptidase 4, used by MERS-CoV [9] . However, four essential structural proteins, i.e., Spike protein (S), Envelope protein (E), Membrane protein (M), and Nucleocapsid protein (N) are found in SARS-CoV-2 and to generate the major components of the virus particle, polyprotein processing is an essential mechanism [10] . The polyproteins are cleaved and transformed into mature nonstructural proteins by the Main Proteases, 3CL protease and responsible for playing a role in replication/transcription process that's why main protease could be an effective drug targets. [11, 12] .

Many efforts are ongoing around the world, but preventive vaccine development usually takes a long time and there are no specific, clear treatment strategies as of now. In the present situation, finding a therapy appropriate for COVID-19 is of paramount importance to reduce the catastrophic effect of the ongoing pandemic. Depending on the target, therapies against SARS-CoV-2 can be divided into two categories: the first acts on the human immune system or human cells, and the second acts on the coronavirus itself [13, 14] . Therapies based on the immune system include blocking the signaling pathways of human cells that include ACE2 receptor protein on the surface of cells required for virus replication. In the case of therapies based on the virus, the retroviral RNA genome encodes for most of the three enzymes essential for virus replication: (i) viral protease (PR), (ii) reverse transcriptase (RT), (iii) integrase (IN) and as of now these three are mainly used as drug targets [15] [16] [17] [18] . In contrast, some of the best characterized, conserved drug targets of coronaviruses are the main protease proteins (MPPs) [19, 20] . Moreover, Inhibition of the activity of MPP would block viral replication, and it would J o u r n a l P r e -p r o o f also be nontoxic, as human proteases with similar cleavage specificity have already been reported [21, 22] .

In addition, various viral protease inhibitors can inhibit proteases and reduce HIV and HCV to undetectable levels which employ aspartyl and serine proteases, respectively. Some of these drugs are now being repurposed for the treatment of COVID-19, which is also possesses a MPP [23, 24, [25] [26] [27] [28] . A computational drug repurposing study has previously shown that many more drugs including Lopinavir and Ritonavir (also HIV-1 protease inhibitors) are capable of inhibiting SARS-CoV MPP and, therefore, could serve as a homologous target, as the previous Pharmacophore modeling is also impossible if the target structure or ligands are unknown.

Conversely, structure-based virtual screening involves the docking of candidate ligands into a protein target followed by the application of a scoring function to estimate the binding affinity between the target molecules [38, 39] . The pharmaceutical industry now routinely practices examining the effects of a potential drug candidate against particular diseases/pathogens due to its reliability and efficacy [40] [41] [42] . Additionally, computational biology could assist in the field of structural biology, lead molecule optimization, potential drug candidate screening, studying drug surface binding patterns, providing a hypothesis for X-ray crystallography to study the substrates and inhibitors, and establishing a combinatorial library [43, 44] . Thus, computational biology could definitely be utilized for repurposing molecules for the treatment of COVID-19.

Repurposing approved drugs against the COVID-19 epidemic also has several advantages, which can help to rapidly identify treatment options [45] . Approved or candidate drugs with repurposing potential as antiviral agents exist for a number of emerging viruses for which urgent, cost-effective therapeutic solutions are required, including influenza virus [46] , Ebola [47] , HCV 

The MPP structures of SARS-CoV-2 (PDB ID: 6LU7 and PDB ID: 6Y2E) and HCV (PDB ID: 2P59) were retrieved from the NCBI and RCSB Protein Data Bank (PDB) [59, 60] . The approved MPP inhibitors against HIV and HCV were prioritized for the study. The PDB format for the approved MPP inhibitors was retrieved from the DrugBank database of NCBI (Table S1 ). For the selection of FDA-approved and widely suggested MPP inhibitors, we used the 'Drug.com' database (https://www.drugs.com/drug-class/protease-inhibitors.html). Furthermore, the derivative molecules of the topmost screened MPP inhibitors were collected from the PubChem database (Table S2) . Moreover, Favipiravir (DB12466), and alpha-ketoamide (CID 6482451)

were also retrieved from the DrugBank database. Remdesivir (DB14761), an approved RNA dependent RNA polymerase inhibitor, was also retrieved from PubChem database, and employed in our study as control group of other MPP.

AutoDockVina software was used for molecular docking experiments, which is now being widely used for screening effective therapeutics against the specific drug target of deadly pathogens [60] [61] [62] . Prior to molecular docking, the crystal structure of MPP was cleaned up using PyMOL [63] , as it was in a complex structure with an inhibitor. identify the involved amino acids with their interactive position in the docked molecules [64] .

Discovery Studio and PyMOL were used to visualize and analyze the ligand molecule interactions with the viral proteins [63, 65] .

To determine the drug surface hotspot of SARS-CoV-2 MPP, the MPP and MPP inhibitors structure were analyzed by LigPlot+, Discovery Studio, and PyMOL. The alpha-ketoamide inhibitor, recently suggested by Linlin Zhang for the treatment of COVID-19, served as the positive control for the study [66, 67] . The molecular docking approach was employed to study the binding pattern of alpha-ketoamide, Favipiravir, and RdRp inhibitor remdesivir with the MPP of SARS-CoV-2, and the results enabled a comparative structural analysis of screened MPP inhibitors and their derivatives. The conservancy pattern of the predicted drug-binding hotspot was analyzed through multiple sequence alignment of homologous MPPs of SARS-CoV-2. All the sequences of the MPP structure deposited in the PDB were retrieved, and multiple sequence alignment was performed using Clustal Omega [68] .

To assess the ADME properties of the topmost candidates for the MPP inhibitors, the SwissADME portal was used. [69] . The SwissADME portal is an online platform that is being used successfully to evaluate the pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of possible drug candidates [70] . This study examined the physico-chemical parameters (formula molecular weight, molar refractivity, total polar surface area (TPSA)), absorption, blood-brain barrier (BBB) permeability, and P-gp substrates, were also investigated for putative MPP drug candidates.

MD simulation was employed to analyze the protein-inhibitor complexes. In the MD simulation, successive iterations were generated by the integration of Newton's low, providing insights into the positions and velocities of each molecule variation over time in the system [71] . In this study, MD simulation was performed by LARMD tools to analyze the MPP in complex with the top 5 predicted drugs and the topmost analog, and the time interval was set to 4 ns, with the influence of water [72] . AMBER16 was the force field, and the minimizations were performed by the Sander module in the AMBER program [73] . In the 4-step minimization, the 2000-step steepest descent method along with the 3000-step conjugated gradient method were adopted, and the system was heated from 10 K to 300 K in 30 ps. Finally, all the atoms were relaxed at 300 K by applying the periodic boundary condition [72] . Moreover, the ligand-receptor root mean square deviation (RMSD), number of H-bonds, and calculation of MM/PB(GB)SA binding free energies are descriptors that were adopted to assess the stability of protein inhibitor complexes during the MD simulation.

All of the retrieved PDB structures of approved MPP inhibitors were prepared and optimized to allow the molecular docking experiment (Table S1 ). Widely used common MPP inhibitors of HCV and HIV (https://www.drugs.com/drug-class/protease-inhibitors.html) were prioritized in the study [74] . There were seven HIV MPP inhibitors (Amprenavir, Ritonavir, Nelfinavir, Indinavir, Darunavir, Fosamprenavir, and Saquinavir) and six HCV inhibitors (Paritaprevir, Grazoprevir, Glecaprevir, Lopinavir, Telaprevir, and Boceprevir), as well as Sunaprevir, Atazanavir, and Lopinavir. All of these MPP inhibitors were employed for molecular docking, and the scoring function of AutoDockVina was utilized to predict the interaction between the above-mentioned ligands and the MPP of SARS-CoV-2 (PDB ID: 6LU7). Paritaprevir, an HCV MPP inhibitor, was found to have the highest negative binding energy (-10.9 kcal/mol) when interacting with the MPP of SARS-CoV-2 (Table 1a and were also found to be the topmost MPP inhibitors with high binding affinities ( Fig. 2, and Fig. 3 ).

Approximately 98% of the structural analogs of Paritaprevir interacting with the MPP of SARS-CoV-2 showed a higher negative binding energy (>-10 kcal/mol) than Paritaprevir interacting with the MPP of SARS-CoV-2 (Table S4) (Table 2 and Fig. 4 ).

To determine common drug surface hotspots of the MPP in SARS-CoV-2, molecular docking interaction of MPP with its inhibitors including control groups were analyzed. Here, basically involved amino acid residues with their respective position were prioritized to target the hotspot of maximum MPP inhibitors against the MPP of SARS-CoV-2. Five approved MPP inhibitors, J o u r n a l P r e -p r o o f such as, Paritaprevir, Glecaprevir, Nelfinavir, Lopinavir, and Lopinavir were isolated for the best ligand molecules bound to the MPP of SARS-CoV-2 from docking study, and these interactions were employed for hotspots analysis (Table S1 ). Moreover, interaction of MPP with Paritaprevir derivatives with highest binding energy were also analyzed to understand the common drug surface hotspots on the MPP of SARS-CoV-2 (Table 1b) Moreover, another MPP structure (PDB ID: 6Y2E), reported for alpha-ketoamide inhibitors, was also docked with the topmost MPP inhibitors found from docking study, and Lopinavir showed a similar binding pattern to Paritaprevir for both MPP structures of SARS-CoV-2 (Table 1b and   Table 2 ). Additionally, the binding pattern of remdesivir (T25, T26 these sequences revealed that all the residues predicted as the hotspot of drug binding were conserved (File S1). Multiple sequence alignment revealed no reported mutations or amino acid changes at the drug hotspot positions which revealed the higher conservancy level in the hotspot region. However, three structures (6XB0, 6XB1, and 6XG2) were found to contain X instead of C at position 145. X represents an unknown residue in the protein sequence, which may be due

to the poor quality of the protein sequence.

The physico-chemical parameters, lipophilicity, pharmacokinetics properties, and water solubility were studied for the topmost putative MPP inhibitors (Paritaprevir, Glecaprevir, Nelfinavir, Lopinavir, and Lopinavir) and the derivatives of Paritaprevir (Table 3 and Table S5 ).

The formula, molecular weight, molar refractivity, and TPSA were determined. The lipophilicity and partition coefficient between n-octanol and water (log Po/w) were also calculated by using five common freely available predictive models (XLOGP3, WLOGP, MLOGP, SILICOS-IT, and iLOGP) [76] . The results of the drug interaction with CYP indicated that only Paritaprevir had an inhibitory effect on CYP3A4, while Glecaprevir showed no interaction with the CYP isoforms. Moreover, the cytochromes CYP1A2, CYP2C9, and CYP2D6 had no interaction with the top putative MPP inhibitors. Additionally, there was no interaction possibility of the top Paritaprevir derivatives with the cytochromes CYP1A2, CYP2C19, CYP2C9, or CYP2D6 (Table   S5 ). Additionally, GI absorption was low in the case of Paritaprevir, Glecaprevir, Nelfinavir, and

Lopinavir and the top Paritaprevir derivatives. BBB permeability was also calculated by BOILED-Egg models [77] , and no BBB permeability was detected among putative MPP inhibitors and Paritaprevir derivatives. This study revealed the water solubility levels of Paritaprevir (1.38e-07 mg/ml; 1.81e-10 mol/l), Glecaprevir (9.22e-06 mg/ml; 1.10e-08 mol/l), Nelfinavir (3.11e-05 mg/ml; 5.48e-08 mol/l), Lopinavir (1.21e-06 mg/ml; 1.61e-09 mol/l), and Lopinavir (5.57e-08 mg/ml; 8.85e-11 mol/l). In addition, the top ten derivatives of Paritaprevir were also subjected to ADME analysis, and the details of the analysis are included in Table S5 .

MPP of SARS-CoV-2 complexed with Paritaprevir, Glecaprevir, Nelfinavir, Lopinavir, Lopinavir, and the topmost predicted analog were employed to molecular dynamic simulation study for checking the structural stability at nanosecond scaled cellular environment (Result shown in Table 4 ). The RMSD value of the topmost predicted analog showed constant binding pattern during the time frame. All of the complex structure of MPP molecules with inhibitors were below 2 Å (Fig. 6a) . Three drugs molecules, such as, Nelfinavir, Lopinavir, and Lopinavir, Here, drug repurposing with the molecular docking approach was employed for comprehensive screening and analysis of the putative drug candidates against SARS-CoV-2. Moreover, to determine the common drug surface hotspots in the MPP of SARS-CoV-2, different recently studied MPP inhibitors of SARS-CoV-2, such as alpha-ketoamide, and Favipiravir [84] [85] [86] , were also investigated with the approved MPP inhibitors and their derivatives.

The SARS-CoV-2 main protease is an attractive drug target for pharmacists because of its essential role in processing viral RNA-encoded polyproteins to yield functional viral proteins [87] . Due to the dissimilarity with human proteases, targeting this enzyme may prevent maturation of the viral particle before exiting the host cell [88] . Shamsi and his colleagues [89] also utilized a structure-based drug design approach to screen the existing pool of FDA-approved drugs against SARS-CoV-2 MPP. The study revealed Glecaprevir and maraviroc as potential inhibitors of SARS-CoV-2 main protease. In another study, Sk et al. (2020) suggested that alphaketoamide could be used as a lead compound in the development of drugs targeting SARS-CoV-2 due to its better binding affinity than other retroviral drugs, including darunavir and Lopinavir.

Moreover, membrane fusion of coronavirus with the host cell is triggered by proteolysis of the spike protein [91, 92] . Therefore, the prevention of spike protein trimming in the same treatment may open the possibility for the immune system to present the virus and generate a response in the host [93] . From the molecular docking studies, it was found that Paritaprevir, Glecaprevir, Nelfinavir, Lopinavir, and Lopinavir could be potential inhibitors of SARS-CoV-2 MPP, and Lopinavir has been previously reported by different studies for the treatment of COVID-19 [94] . Paritaprevir [95] , Glecaprevir [96] , Nelfinavir [97] , and Lopinavir [98] have already been approved for the treatment of HIV or HCV [99] , and the results of this study indicated that they could be potential drug candidates for SARS-CoV-2 rather than Lopinavir. Again, the present study also 

The top screened drug candidates from MPP inhibitors and their derivatives were also employed for ADME analysis. Physico-chemical parameters, lipophilicity, pharmacokinetics properties, and water solubility were studied, which contribute to the analysis of ADME properties. Menon and his coworkers [104] conducted two parallel double-blind, placebo-controlled phase 1 group studies in healthy volunteers. Single-dose study participants (n = 87) were subjected to one-time administration of Paritaprevir, while multiple-dose study participants (n = 38) received in any liver function tests. In the present study, we also analyzed the ADME properties of Paritaprevir, which did not show any undesirable consequences that could reduce its druglikeness properties. The study of CYP isoform inhibition revealed that the suggested MPP inhibitors and Paritaprevir derivatives had few possibilities to interact with the CYP isoforms.

However, Paritaprevir is predominantly metabolized by CYP3A4 and, to a lesser extent, CYP3A5 [106] . CYP3A4 metabolizes more than 50% of clinically used drugs, and it is most abundant in human liver [107] . Inactivation of CYP3A4 may be responsible for drug toxicity through enhanced exposure to other coadministered drugs [108] . However, proper clinical management may enable professionals to significantly minimize the negative consequences of CYP3A4 inhibition [109] . Thus, proper clinical approaches, such as the rational use of drugs, use of a safe drug combination regimen, dose adjustment, and discontinuation of therapy when toxic drug interactions occur are necessary, are required for using Paritaprevir in clinical phase trials.

Furthermore, therapeutic drug monitoring and predicting the risks for potential drug-drug interactions (both qualitatively and quantitatively) should also be prioritized [109] . In the present study, BBB permeability and water solubility of putative MPP inhibitors were also calculated.

There was no BBB permeability for the screened MPP inhibitors and Paritaprevir derivatives.

At present, computational approaches have been widely adopted for the prediction of potential drugs that could play a crucial role in further drug development. Thus, it is important to predict J o u r n a l P r e -p r o o f accurate protein-inhibitor complexes, which can be achieved by MD simulation. By this MD simulation, the docked pose predicted by molecular docking approaches could be analyzed to predict whether it is stable or not in an aqueous environment [110] . In this study, MD simulation was also employed to assess the stability of MPP in complex with Paritaprevir and its analog, Glecaprevir, Nelfinavir, Lopinavir, and Lopinavir through the analysis of RMSD, H-bonds, and the binding free energies. All the complexes were stable, as the RMSD was below 2 Å.

Paritaprevir was found to cause higher conformational changes in MPPs than the others, while its analog was found to form a stable complex with MP. The stability was achieved by the much greater number of H-bonds. Both Paritaprevir and its analog would be more effective for the inhibition of the MPP of SARS-CoV-2, followed by Glecaprevir and Nelfinavir (Table 4 ).

However, Lopinavir and Lopinavir would be less effective for the inhibition of MP.

Paritaprevir, also known as ABT-450, was approved in 2014 for the treatment of HCV genotype 1 and in 2015 for genotype 4 [105] . It showed promising results in combination with Ritonavir and ribavirin and caused a 95% sustained virologic response against HCV genotype 1 [111] . Side effects of Paritaprevir are relatively uncommon, though it is sometimes associated with fatigue, asthenia nausea, insomnia, pruritus, and other skin reactions [106] . Approximately 88% of the drug is eliminated through feces, while the remainder is eliminated via the urine. In a phase 3 trial performed by Poordad et al. [112] , less than 1% of the subjects discontinued treatment as a result of side effects in a combination therapy. Paritaprevir does not require dose adjustment for patients with renal impairment [106] . Nevertheless, caution should be taken for the repurposing of Paritaprevir to treat COVID-19 patients with severe hepatic impairment, diabetes, or cardiac diseases to minimize the risk of potential toxicity.

The results concluded that Paritaprevir and its analog (CID 131982844) could be a more J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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4R,6S,7Z,14S,18R)-N-cyclopropylsulfonyl-18-(3,9-difluorophenanthridin-6-yl)oxy-14-[(1-methylpyrazole-4-carbonyl)amino]-2,15-dioxo-3,16-diazatricyclo

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methylpyrazine-2-carbonyl)amino]-3,9-dioxo-6-phenanthridin-6-yloxy-2,8-diazatricyclo