Computational design for the development of natural molecules as compelling inhibitors against the target SARS-CoV-2: An in-silico attempt

Nagarjuna Palathoti; Kalirajan Rajagopal; Gowramma Byran; Kannan Raman; Edwin Jose; Manikandan Gurunathan

doi:10.7324/JAPS.2023.134301

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Abstract

A threat to the global human population has been established by the COVID-19 pandemic in 2020 and it is quite challenging to identify innovative medications in this epidemic. These are zoonotic and can potentially create massive outbreaks of illnesses that can result in morbidity and death. As a consequence, natural therapies for the anticipation and dealing of COVID-19 are widely acknowledged as a quick means to find successful therapeutic choices that can be found through in-silico drug screening tests. RNA-dependent RNA polymerase (RdRp), a vital precursor involved in the virus’s life cycle, is present in SARS-CoV-2. Blocking the formation of the RdRp–RNA complex inhibits viral replica and boosts the immune response of the host. In our present research, with the use of a SuperNatural Database, we started the high-throughput virtual screening method to recognize inhibitors aiming for SARS-CoV-2 RdRp. According to extra-precision docking data, two compounds, SN00293542 and SN00391842 had −14.79 and −14.65 kcal/mol docking scores, respectively. In addition, Prime molecular mechanics generalized bond surface area research has identified hydrophobic energy and Van der Waal energy footings as significant contributions towards total binding free energy. Additionally, a hundred nanosecond Molecular dynamics simulation of the SN00391842/7D4F complex was run to determine its dynamic behavior.

Citation:

Palathoti N, Rajagopal K, Byran G, Raman K, Jose E, Gurunathan M. Computational design for the development of natural molecules as compelling inhibitors against the target SARS-CoV-2: An in-silico attempt. J Appl Pharm Sci, 2023; 13(Suppl 1):034–040. https://doi.org/10.7324/JAPS.2023.134301

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA, Sacerdoti FD, Salmon JK. Scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing, LLC, New York, 2006, pp 84-es. https://doi.org/10.1145/1188455.1188544
Dar AM, Mir S. Molecular docking: approaches, types, applications and basic challenges. J Anal Bioanal Tech, 2017; 8(2):1-3. https://doi.org/10.4172/2155-9872.1000356
Dunkel M, Fullbeck M, Neumann S, Preissner R. Supernatural: a searchable database of available natural compounds. Nucleic Acids Res, 2006; 34(suppl_1):D678-83. https://doi.org/10.1093/nar/gkj132
Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG. A smooth particle mesh Ewald method. J Chem Phys, 1995; 103:8577-93. https://doi.org/10.1063/1.470117
Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY, Wang L, Lupyan D, Dahlgren MK, Knight JL, Kaus JW, Cerutti DS, Krilov G, Jorgensen WL, Abel R, Friesner RA. OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput, 2016; 12:281-96. https://doi.org/10.1021/acs.jctc.5b00864
Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phy, 1983; 79:926-35. Kalirajan R. Activity of some novel chalcone substituted 9-anilinoacridines against coronavirus (COVID-19): a computational approach. Coronaviruses, 2020; 1(1):13-22. https://doi.org/10.2174/2666796701999200625210746
Kalirajan R, Gaurav K, Pandiselvi A, Gowramma B, Sankar S. Novel thiazine substituted 9-anilinoacridines: synthesis, antitumour activity and structure activity relationships. Anticancer Agents Med Chem, 2019b; 19:1350-8. https://doi.org/10.2174/1871520619666190408134224
Kalirajan R, Gowramma B, Srikanth J, Vadivelan R. Activity of phytochemical constituents of black pepper, ginger and garlic against coronavirus (COVID-19): an in-silico approach. Int J Health Allied Sci, 2020; 9:S43-50. https://doi.org/10.4103/ijhas.IJHAS_55_20
Kalirajan R, Muralidharan V, Jubie S, Gowramma B, Gomathy S, Sankar S, Elango K. Synthesis of some novel pyrazole substituted 9-anilinoacridine derivatives and evaluation for their antioxidant and cytotoxic activities. J Heterocycl Chem, 2012a; 49:748-54. https://doi.org/10.1002/jhet.848
Kalirajan R, Pandiselvi A, Gowramma B, Balachandran P. In-silico design, ADMET screening, MM-GBSA binding free energy of some novel isoxazole substituted 9-anilinoacridines as HER2 inhibitors targeting breast cancer. Curr Drug Res Rev, 2019a; 11:118-28. https://doi.org/10.2174/2589977511666190912154817
Kalirajan R, Sankar S, Jubie S, Gowramma B. Molecular docking studies and in-silico ADMET screening of some novel oxazine substituted 9-anilinoacridines as topoisomerase II inhibitors. Indian J Pharm Educ Res, 2017; 51:110-5. https://doi.org/10.5530/ijper.51.1.15
Kalirajan R, Vivekkulshrestha V, Sankar S, Jubie S. Docking studies, synthesis, characterization of some novel oxazine substituted 9-anilinoacridine derivatives and evaluation for their anti-oxidant and anticancer activities as topoisomerase II inhibitors. Eur J Med Chem, 2012b; 56:217-24. https://doi.org/10.1016/j.ejmech.2012.08.025
Kalirajan R, Vivekkulshrestha V, Sankar S. Synthesis, characterization and evaluation for antitumour activity of some novel oxazine substituted 9-anilinoacridines and their 3D-QSAR studies. Indian J Pharm Sci, 2018; 80:921-9. https://doi.org/10.4172/pharmaceutical-sciences.1000439
Kumar R, Harilal S, Al-Sehemi AG, Pannipara M, Behl T, Mathew GE, Mathew B. COVID-19 and domestic animals: exploring the species barrier crossing, zoonotic and reverse zoonotic transmission of SARS-CoV-2. Curr Pharm Des, 2021; 27:1194-201. https://doi.org/10.2174/1381612826666201118112203
Lakshmi SP, Suresh M. Factors influencing the epidemiological characteristics of pandemic COVID-19: a TISM approach. Int J Healthc Manag, 2020; 13:89-98. https://doi.org/10.1080/20479700.2020.1755804
Lei J, Kusov Y, Hilgenfeld R. Nsp3 of coronaviruses: structures and functions of a large multi-domain protein. Antiviral Res, 2018; 149:58-74. https://doi.org/10.1016/j.antiviral.2017.11.001
Lim KP, Ng LF, Liu DX. Identification of a novel cleavage activity of the first papain-like proteinase domain encoded by open reading frame 1a of the coronavirus avian infectious bronchitis virus and characterization of the cleavage products. J Virol, 2000; 74:1674-85. https://doi.org/10.1128/JVI.74.4.1674-1685.2000
Martyna GJ, Klein ML, Tuckerman M. Nose-Hoover chains: the canonical ensemble via continuous dynamics. J Chem Phys, 1992; 97:2635-43. https://doi.org/10.1063/1.463940
Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phys, 1994; 101:4177-89. https://doi.org/10.1063/1.467468
Mielech AM, Chen Y, Mesecar AD, Baker SC. Nidovirus papain-like proteases: multifunctional enzymes with protease, deubiquitinating and deISGylating activities. Virus Res, 2014; 194:184-90. https://doi.org/10.1016/j.virusres.2014.01.025
Naresh P, Selvaraj A, Shyam Sundar P, Murugesan S, Sathianarayananan S, Namboori PKK, Jubie S. Targeting a conserved pocket (n-octylb-Dglucoside) on the dengue virus envelope protein by small bioactive molecule inhibitors. J Biomol Struct Dyn, 2020; 0:1-13.
Osipiuk J, Azizi SA, Dvorkin S, Endres M, Jedrzejczak R, Jones KA, Kang S, Kathayat RS, Kim Y, Lisnyak VG, Maki SL, Nicolaescu V, Taylor CA, Tesar C, Zhang YA, Zhou Z, Randall G, Michalska K, Snyder SA, Dickinson BC, Joachimiak A. Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat Commun, 2021; 12:743. https://doi.org/10.1038/s41467-021-21060-3
Raj R. Analysis of non-structural proteins, NSPs of SARS-CoV-2 as targets for computational drug designing. Biochem Biophys Rep, 2021; 25:100847. https://doi.org/10.1016/j.bbrep.2020.100847
Rajagopal K, Varakumar P, Aparna B, Byran G, Jupudi S. Identification of some novel oxazine substituted 9-anilinoacridines as SARS-CoV-2 inhibitors for COVID-19 by molecular docking, free energy calculation and molecular dynamics studies. J Biomol Struct Dyn, 2021; 39(15):5551-62. https://doi.org/10.1080/07391102.2020.1798285
Rajagopal K, Varakumar P, Baliwada A, Byran G. The activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in-silico approach. Futur J Pharm Sci, 2019; 6:104. https://doi.org/10.1186/s43094-020-00126-x
Ram TS, Munikumar M, Raju VN, Devaraj P, Boiroju NK, Hemalatha R, Prasad PV, Gundeti M, Sisodia BS, Pawar S, Prasad GP. In silico evaluation of the compounds of the ayurvedic drug, AYUSH-64, for the action against the SARS-CoV-2 main protease. J Ayu Integr Med, 2022; 13(1):100413. https://doi.org/10.1016/j.jaim.2021.02.004
Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des, 2013; 27:221-34. https://doi.org/10.1007/s10822-013-9644-8
Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput, 2010; 6(5):1509-19. https://doi.org/10.1021/ct900587b
Sukumaran S, Meghna M, Sneha S, Arjun B, Sathianarayanan S, Saranya TS. Insilico analysis of acridone against TNF-a and PDE4 targets for the treatment of psoriasis. Int J Res Pharm Sci, 2020; 11:1251-9. https://doi.org/10.26452/ijrps.v11iSPL4.4286
Umakanthan S, Sahu P, Ranade AV, Bukelo MM, Rao JS, Abrahao-Machado LF, Dahal S, Kumar H, Kv D. Origin, transmission, diagnosis and management of coronavirus disease 2019 (COVID-19). Postgrad Med J, 2020; 96:753-58.
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Yadav R, Chaudhary JK, Jain N, Chaudhary PK, Khanra S, Dhamija P, Sharma A, Kumar A, Handu S. Role of structural and non-structural proteins and therapeutic targets of SARS-CoV-2 for COVID-19. Cells, 2021; 10:1-16. https://doi.org/10.3390/cells10040821
Yin W, Luan X, Li Z, Zhou Z, Wang Q, Gao M, Wang X, Zhou F, Shi J, You E, Liu M. Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin. Nat Struct Mol Biol, 2021; 28(3):319-25. https://doi.org/10.1038/s41594-021-00570-0

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Adithya J, Nair B, Aishwarya TS, Nath LR. The plausible role of Indian traditional medicine in combating coronavirus (SARS-CoV 2): a mini-review. Curr Pharm Biotechnol, 2021; 22(7):906-19. https://doi.org/10.2174/1389201021666200807111359

Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA, Sacerdoti FD, Salmon JK. Scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing, LLC, New York, 2006, pp 84-es. https://doi.org/10.1145/1188455.1188544

Dar AM, Mir S. Molecular docking: approaches, types, applications and basic challenges. J Anal Bioanal Tech, 2017; 8(2):1-3. https://doi.org/10.4172/2155-9872.1000356

Dunkel M, Fullbeck M, Neumann S, Preissner R. Supernatural: a searchable database of available natural compounds. Nucleic Acids Res, 2006; 34(suppl_1):D678-83. https://doi.org/10.1093/nar/gkj132

Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG. A smooth particle mesh Ewald method. J Chem Phys, 1995; 103:8577-93. https://doi.org/10.1063/1.470117

Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY, Wang L, Lupyan D, Dahlgren MK, Knight JL, Kaus JW, Cerutti DS, Krilov G, Jorgensen WL, Abel R, Friesner RA. OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput, 2016; 12:281-96. https://doi.org/10.1021/acs.jctc.5b00864

Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phy, 1983; 79:926-35. Kalirajan R. Activity of some novel chalcone substituted 9-anilinoacridines against coronavirus (COVID-19): a computational approach. Coronaviruses, 2020; 1(1):13-22. https://doi.org/10.2174/2666796701999200625210746

Kalirajan R, Gaurav K, Pandiselvi A, Gowramma B, Sankar S. Novel thiazine substituted 9-anilinoacridines: synthesis, antitumour activity and structure activity relationships. Anticancer Agents Med Chem, 2019b; 19:1350-8. https://doi.org/10.2174/1871520619666190408134224

Kalirajan R, Gowramma B, Srikanth J, Vadivelan R. Activity of phytochemical constituents of black pepper, ginger and garlic against coronavirus (COVID-19): an in-silico approach. Int J Health Allied Sci, 2020; 9:S43-50. https://doi.org/10.4103/ijhas.IJHAS_55_20

Kalirajan R, Muralidharan V, Jubie S, Gowramma B, Gomathy S, Sankar S, Elango K. Synthesis of some novel pyrazole substituted 9-anilinoacridine derivatives and evaluation for their antioxidant and cytotoxic activities. J Heterocycl Chem, 2012a; 49:748-54. https://doi.org/10.1002/jhet.848

Kalirajan R, Pandiselvi A, Gowramma B, Balachandran P. In-silico design, ADMET screening, MM-GBSA binding free energy of some novel isoxazole substituted 9-anilinoacridines as HER2 inhibitors targeting breast cancer. Curr Drug Res Rev, 2019a; 11:118-28. https://doi.org/10.2174/2589977511666190912154817

Kalirajan R, Sankar S, Jubie S, Gowramma B. Molecular docking studies and in-silico ADMET screening of some novel oxazine substituted 9-anilinoacridines as topoisomerase II inhibitors. Indian J Pharm Educ Res, 2017; 51:110-5. https://doi.org/10.5530/ijper.51.1.15

Kalirajan R, Vivekkulshrestha V, Sankar S, Jubie S. Docking studies, synthesis, characterization of some novel oxazine substituted 9-anilinoacridine derivatives and evaluation for their anti-oxidant and anticancer activities as topoisomerase II inhibitors. Eur J Med Chem, 2012b; 56:217-24. https://doi.org/10.1016/j.ejmech.2012.08.025

Kalirajan R, Vivekkulshrestha V, Sankar S. Synthesis, characterization and evaluation for antitumour activity of some novel oxazine substituted 9-anilinoacridines and their 3D-QSAR studies. Indian J Pharm Sci, 2018; 80:921-9. https://doi.org/10.4172/pharmaceutical-sciences.1000439

Kumar R, Harilal S, Al-Sehemi AG, Pannipara M, Behl T, Mathew GE, Mathew B. COVID-19 and domestic animals: exploring the species barrier crossing, zoonotic and reverse zoonotic transmission of SARS-CoV-2. Curr Pharm Des, 2021; 27:1194-201. https://doi.org/10.2174/1381612826666201118112203

Lakshmi SP, Suresh M. Factors influencing the epidemiological characteristics of pandemic COVID-19: a TISM approach. Int J Healthc Manag, 2020; 13:89-98. https://doi.org/10.1080/20479700.2020.1755804

Lei J, Kusov Y, Hilgenfeld R. Nsp3 of coronaviruses: structures and functions of a large multi-domain protein. Antiviral Res, 2018; 149:58-74. https://doi.org/10.1016/j.antiviral.2017.11.001

Lim KP, Ng LF, Liu DX. Identification of a novel cleavage activity of the first papain-like proteinase domain encoded by open reading frame 1a of the coronavirus avian infectious bronchitis virus and characterization of the cleavage products. J Virol, 2000; 74:1674-85. https://doi.org/10.1128/JVI.74.4.1674-1685.2000

Martyna GJ, Klein ML, Tuckerman M. Nose-Hoover chains: the canonical ensemble via continuous dynamics. J Chem Phys, 1992; 97:2635-43. https://doi.org/10.1063/1.463940

Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phys, 1994; 101:4177-89. https://doi.org/10.1063/1.467468

Mielech AM, Chen Y, Mesecar AD, Baker SC. Nidovirus papain-like proteases: multifunctional enzymes with protease, deubiquitinating and deISGylating activities. Virus Res, 2014; 194:184-90. https://doi.org/10.1016/j.virusres.2014.01.025

Naresh P, Selvaraj A, Shyam Sundar P, Murugesan S, Sathianarayananan S, Namboori PKK, Jubie S. Targeting a conserved pocket (n-octylb-Dglucoside) on the dengue virus envelope protein by small bioactive molecule inhibitors. J Biomol Struct Dyn, 2020; 0:1-13.

Osipiuk J, Azizi SA, Dvorkin S, Endres M, Jedrzejczak R, Jones KA, Kang S, Kathayat RS, Kim Y, Lisnyak VG, Maki SL, Nicolaescu V, Taylor CA, Tesar C, Zhang YA, Zhou Z, Randall G, Michalska K, Snyder SA, Dickinson BC, Joachimiak A. Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat Commun, 2021; 12:743. https://doi.org/10.1038/s41467-021-21060-3

Raj R. Analysis of non-structural proteins, NSPs of SARS-CoV-2 as targets for computational drug designing. Biochem Biophys Rep, 2021; 25:100847. https://doi.org/10.1016/j.bbrep.2020.100847

Rajagopal K, Varakumar P, Aparna B, Byran G, Jupudi S. Identification of some novel oxazine substituted 9-anilinoacridines as SARS-CoV-2 inhibitors for COVID-19 by molecular docking, free energy calculation and molecular dynamics studies. J Biomol Struct Dyn, 2021; 39(15):5551-62. https://doi.org/10.1080/07391102.2020.1798285

Rajagopal K, Varakumar P, Baliwada A, Byran G. The activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in-silico approach. Futur J Pharm Sci, 2019; 6:104. https://doi.org/10.1186/s43094-020-00126-x

Ram TS, Munikumar M, Raju VN, Devaraj P, Boiroju NK, Hemalatha R, Prasad PV, Gundeti M, Sisodia BS, Pawar S, Prasad GP. In silico evaluation of the compounds of the ayurvedic drug, AYUSH-64, for the action against the SARS-CoV-2 main protease. J Ayu Integr Med, 2022; 13(1):100413. https://doi.org/10.1016/j.jaim.2021.02.004

Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des, 2013; 27:221-34. https://doi.org/10.1007/s10822-013-9644-8

Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput, 2010; 6(5):1509-19. https://doi.org/10.1021/ct900587b

Sukumaran S, Meghna M, Sneha S, Arjun B, Sathianarayanan S, Saranya TS. Insilico analysis of acridone against TNF-a and PDE4 targets for the treatment of psoriasis. Int J Res Pharm Sci, 2020; 11:1251-9. https://doi.org/10.26452/ijrps.v11iSPL4.4286

Umakanthan S, Sahu P, Ranade AV, Bukelo MM, Rao JS, Abrahao-Machado LF, Dahal S, Kumar H, Kv D. Origin, transmission, diagnosis and management of coronavirus disease 2019 (COVID-19). Postgrad Med J, 2020; 96:753-58.

V'kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol, 2021; 19:155-70. https://doi.org/10.1038/s41579-020-00468-6

WHO. 2023. Available via https:// covid19.who.int/region/searo/ country/in (Accessed 03 January 2023).

Yadav R, Chaudhary JK, Jain N, Chaudhary PK, Khanra S, Dhamija P, Sharma A, Kumar A, Handu S. Role of structural and non-structural proteins and therapeutic targets of SARS-CoV-2 for COVID-19. Cells, 2021; 10:1-16. https://doi.org/10.3390/cells10040821

Yin W, Luan X, Li Z, Zhou Z, Wang Q, Gao M, Wang X, Zhou F, Shi J, You E, Liu M. Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin. Nat Struct Mol Biol, 2021; 28(3):319-25. https://doi.org/10.1038/s41594-021-00570-0