Molecular Docking and Molecular Dynamics Aided Virtual Search of OliveNet™ Directory for Secoiridoids to Combat SARS-CoV-2 Infection and Associated Hyperinflammatory Responses

Molecular docking and molecular dynamics aided virtual search of OliveNet™ directory identified potential secoiridoids that combat SARS-CoV-2 entry, replication, and associated hyperinflammatory responses. OliveNet™ is an active directory of phytochemicals obtained from different parts of the olive tree, Olea europaea (Oleaceae). Olive oil, olive fruits containing phenolics, known for their health benefits, are indispensable in the Mediterranean and Arabian diets. Secoiridoids is the largest group of olive phenols and is exclusive to the olive fruits. Functional food like olive fruits could help prevent and alleviate viral disease at an affordable cost. A systematized virtual search of 932 conformers of 78 secoiridoids utilizing Autodock Vina, followed by precision docking using Idock and Smina indicated that Nüzhenide oleoside (NZO), Oleuropein dimer (OED), and Dihydro oleuropein (DHO) blocked the SARS-CoV-2 spike (S) protein-ACE-2 interface; Demethyloleuropein (DMO), Neo-nüzhenide (NNZ), and Nüzhenide (NZE) blocked the SARS-CoV-2 main protease (Mpro). Molecular dynamics (MD) simulation of the NZO-S-protein-ACE-2 complex by Desmond revealed stability during 50 ns. RMSD of the NZO-S-protein-ACE-2 complex converged at 2.1 Å after 20 ns. During MD, the interaction fractions confirmed multiple interactions of NZO with Lys417, a crucial residue for inhibition of S protein. MD of DMO-Mpro complex proved its stability as the RMSD converged at 1.6 Å. Analysis of interactions during MD confirmed the interaction of Cys145 of Mpro with DMO and, thus, its inhibition. The docking predicted IC50 of NZO and DMO was 11.58 and 6.44 μM, respectively. Molecular docking and dynamics of inhibition of the S protein and Mpro by NZO and DMO correlated well. Docking of the six-hit secoiridoids to IL1R, IL6R, and TNFR1, the receptors of inflammatory cytokines IL1β, IL6, and TNFα, revealed the anti-inflammatory potential except for DHO. Due to intricate structures, the secoiridoids violated Lipinski's rule of five. However, the drug scores of secoiridoids supported their use as drugs. The ADMET predictions implied that the secoiridoids are non-toxic and pose low oral absorption. Secoiridoids need further optimization and are a suitable lead for the discovery of anti-SARS-CoV-2 therapeutics. For the moment, olive secoiridoids presents an accessible mode of prevention and therapy of SARS-CoV-2 infection.

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Novel Coronavirus (SARS-CoV-2) Main Protease: Molecular docking of Puerarin as a Potential inhibitor

10.21203/rs.3.rs-37794/v1 ◽

2020 ◽

Author(s):

Oluwafemi Adeleke Ojo ◽

Adebola Busola Ojo ◽

Odunayo Anthonia Taiwo ◽

Olarewaju M Oluba

Keyword(s):

Molecular Docking ◽

Rna Virus ◽

Drug Candidate ◽

Lipinski’S Rule ◽

Global Pandemic ◽

Main Protease ◽

Lipinski’S Rule Of Five ◽

Novel Coronavirus ◽

Research World ◽

High Binding Affinity

Abstract SARS-CoV-2 a single stranded RNA virus which triggered the global pandemic Coronavirus Disease- 2019 (COVID-2019). It has infected about 2,844,712 patients and brought forth mortality rate to about 201,315 among 216 countries as cited by WHO. Drugs including Chloroquine and Hydroxychloroquine derivatives are being administered in most urgent cases; although, with probable side effects to people with metabolic disorders. Thus, unavailability of authorized drugs and treatment for this pandemic demands the research world to discover natural compounds with potency to cure it. This paper assesses the isoflavonoid puerarin from Pueraria lobata as a possible inhibitor of the main protease of SARS-COV-2 (Mpro) via in silico approach, for example molecular docking, Lipinski’s rule of five and toxicity prediction (ADME). Puerarin revealed high binding affinity with the target site of SARS-CoV-2 main protease. This compound slightly meets the criteria of Lipinski’s rule and does not possess properties that could cause adverse effects in humans thus, making puerarin a potential drug candidate to investigate for its usage against COVID-19.

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Interactions of Alkyl Gallates with SARS-CoV-2 Main Protease: A Molecular Docking Approach

Chemistry Proceedings ◽

10.3390/ecsoc-24-08360 ◽

2020 ◽

Vol 3 (1) ◽

pp. 9

Author(s):

Amalia Stefaniu ◽

Lucia Pintilie ◽

Bujor Albu ◽

Lucia Pirvu

Keyword(s):

Amino Acids ◽

Molecular Docking ◽

Synthetic Compounds ◽

X Ray ◽

Lipinski’S Rule ◽

Alkyl Gallates ◽

Main Protease ◽

Docking Approach ◽

Lipinski’S Rule Of Five ◽

In Silico Methods

Ten natural and semi-synthetic compounds (gallic acid and alkyl gallates) were investigated by in silico methods in order to evaluate their potential inhibitory activity against SAR-CoV-2 using the X-ray structure of SARS-CoV-2 main protease bound to Boceprevir at 1.45 Å (PDB ID: 6WNP). The evaluation of drug-likeness in terms of Lipinski’s Rule of Five and docking results in terms of docking score and interactions with the amino acids residues from the active binding site of the target protein were reported.

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Computational analysis by molecular docking of thirty alkaloid compounds from medicinal plants as potent inhibitors of SARS-CoV-2 main protease

SDRP Journal of Computational Chemistry & Molecular Modelling ◽

10.25177/jccmm.4.4.ra.10699 ◽

2021 ◽

Vol 4 (4) ◽

pp. 487-503

Author(s):

Tunga Kuhana A ◽

◽

Jason T. Kilembe ◽

Aristote Matondo ◽

Khamis M. Yussuf ◽

...

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Medicinal Plants ◽

Computational Analysis ◽

Potential Drug ◽

Lipinski’S Rule ◽

Main Protease ◽

Lipinski’S Rule Of Five ◽

Potential Inhibitors ◽

Therapeutic Profile

Year 2020 has been highly affected by the COVID-19 outbreak. The urgent need for a potent and effective drug for the treatment of this malignancy put pressure on researchers and scientists worldwide to develop a potential drug or a vaccine to resist SARS-CoV-2 virus. We report in this paper the assessment of the efficiency of thirty alkaloid compounds derived from African medicinal plants against the SARS-CoV-2 main protease through molecular docking and bioinformatics approaches. The results revealed four potential inhibitors (ligands 18, 21, 23 and 24) with 12.26 kcal/mol being the highest binding energy. Additionally, in silico drug-likeness and ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties for the four ligands showed a good predicted therapeutic profile of druggability, and fully obey the Lipinski's rule of five as well.

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Natural xanthone compounds as promising drug candidates against COVID-19 - An integrated molecular docking and dynamics simulation study

10.21203/rs.3.rs-102884/v1 ◽

2020 ◽

Author(s):

Shravan Kumar Gunda ◽

Hima Kumari P ◽

Gourav Choudhir ◽

Anuj Kumar ◽

P B. Kavi Kishor ◽

...

Keyword(s):

Molecular Docking ◽

Antiviral Agents ◽

Binding Energies ◽

Dynamics Simulation ◽

Lipinski’S Rule ◽

Drug Candidates ◽

Main Protease ◽

Lipinski’S Rule Of Five ◽

Dynamics Simulations ◽

Potential Inhibitors

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease2019 (COVID-19). SARS-CoV-2 is known for its high pathogenicity and transmission due to thepresence of polybasic cleavage sites. No specific drug is available for the treatment. To identifythe potential inhibitors, we have performed molecular docking against the SARS-CoV-2 mainprotease (6Y84) with fifteen important natural xanthone compounds. The docking results showedall the compounds exhibited good binding energies and interactions with the main protease. Thevalidation of representative docking complexes through molecular dynamics simulations showedthat xanthones binds with a higher binding affinity and lower free energy than the standardligand with Brasixanthone C and Brasixanthone B on 50 ns. Natural xanthone compounds havealso passed the Absorption, Distribution, Metabolism, and Excretion (ADME) property criteriaas well as Lipinski’s rule of five. The present integrated molecular docking and dynamicssimulations study unveil the use of xanthones as potential antiviral agents against SARS-CoV-2.

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Studi In Silico Senyawa 1,4-Naphthalenedione-2-Ethyl-3-Hydroxy sebagai Antiinflamasi dan Antikanker Payudara

ALCHEMY Jurnal Penelitian Kimia ◽

10.20961/alchemy.17.1.43979.83-95 ◽

2021 ◽

Vol 17 (1) ◽

pp. 83

Author(s):

Richa Mardianingrum ◽

Kamiel Roesman Bachtiar ◽

Susanti Susanti ◽

Aas Nuraisah Aas Nuraisah ◽

Ruswanto Ruswanto

Keyword(s):

Breast Cancer ◽

Molecular Dynamics ◽

Molecular Docking ◽

In Silico ◽

The Body ◽

Dynamics Simulation ◽

Lipinski’S Rule ◽

Lipinski’S Rule Of Five ◽

Anti Inflammatory ◽

Cox 1

Inflamasi merupakan suatu respon dari tubuh terhadap adanya cedera maupun infeksi yang ditandai dengan timbulnya kemerahan, demam, bengkak, nyeri dan hilangnya fungsi. Inflamasi berkontribusi terhadap ketidakseimbangan sekresi sitokin yang akan menghambat terjadinya apoptosis pada sel kanker sehingga menyebabkan hiperproliferasi sel. Kanker payudara merupakan salah satu penyakit kanker dengan prevalensi tertinggi di urutan ke dua di dunia. Penelitian terdahulu melaporkan pemberian minyak atsiri rimpang bangle (Zingiber purpureum Roxb.) secara topikal mampu memberikan penghambatan inflamasi yang lebih tinggi daripada triamcinolone, namun spesifik senyawa yang berpotensinya belum diketahui. Tujuan dari penelitian ini, yakni mencari senyawa aktif hasil analisis GCMS minyak atsiri rimpang bangle yang berpotensi sebagai antiinflamasi dan antikanker payudara secara in silico. Metode yang digunakan berupa screening Lipinski’s rule of Five, farmakokinetika dan toksisitas senyawa hasil analisis GC-MS, serta penambatan molekul dan dinamika molekular. Hasil screening dan simulasi penambatan molekul menunjukkan bahwa senyawa 1,4-naphthalenedione-2-ethyl-3-hydroxy dapat berikatan dengan reseptor COX-1 (antiinflamasi), dan hERα (antikanker payudara), namun lebih selektif terhadap reseptor COX-1 dengan nilai energi bebas (ΔG) yang lebih kecil yakni sebesar -7,20 kkal/mol, dibandingkan dengan interaksinya terhadap reseptor Erα yang bernilai -6,00 kkal/mol. Hasil simulasi dinamika molekular menggunakan metode kalkulasi MM-GBSA menunjukkan bahwa kompleks (1,4-naphthalenedione-2-ethyl-3-hydroxy)-(COX-1) memiliki nilai ∆GTOTAL sebesar -24,22 kkal/mol. Nilai ini lebih kecil dibandingkan dengan ∆GTOTAL kompleks (1,4-naphthalenedione-2-ethyl-3-hydroxy)-(hErα) sebesar -8,92 kkal/mol). Hal ini menunjukkan bahwa tingkat afinitas 1,4-naphthalenedione-2-ethyl-3-hydroxy terhadap COX-1 diprediksi lebih baik dan lebih poten sebagai antiinflamasi dibandingkan sebagai antikanker payudara.In Silico Study of 1,4-Naphthalenedione-2-Ethyl-3-Hydroxy Compounds as Anti-inflamation dan Breast Anticancer. Inflammation is a response from the body to injury or infection which is characterized by redness, fever, swelling, pain, and loss of function. Inflammation contributes to the imbalance of cytokine secretion which will inhibit apoptosis in cancer cells, causing cell hyperproliferation. Breast cancer is one of the cancer diseases with the second-highest prevalence in the world. The pioneering works reported that topical application of Bangle (Zingiber purpureum R) was able to provide a higher inhibition of inflammation than triamcinolone, however, the specific potential of the compound was unknown. The purpose of this study is to find active compounds that have the potential to be anti-inflammatory and anti-cancer in the breast using in silico approach. The methods used are screening Lipinski’s Rule of Five, pharmacokinetics and toxicity of compounds from GC-MS analysis and molecular docking, and molecular dynamics. The screening and molecular docking simulation results showed that the compound 1,4-naphthalenedione-2-ethyl-3-hydroxy can bind to COX-1 (anti-inflammatory), and ERα (Estrogen Reseptor α), but was more selective towards COX-1 receptor with a binding affinity (ΔG) -7.20 kcal/mol, compare to its interaction with ERα which is -6.00 kcal/mol. The results of molecular dynamics simulation using the MM-GBSA calculation method show that the complex (1,4-naphthalenedione-2-ethyl-3-hydroxy)-(COX-1) has a value of ∆GTOTAL of -24.22 kcal/mol). This value is smaller than ∆GTOTAL of the complex (1,4-naphthalenedione-2-ethyl-3-hydroxy)-(hErα) of -8.92 kcal/mol. The results indicate that the affinity level of 1,4-naphthalenedione-2-ethyl-3-hydroxy to COX-1 was predicted to be better and more potent as an anti-inflammatory than as an anti-breast cancer.

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Exploring the Potency of Nigella sativa Seed in Inhibiting SARS-CoV-2 Main Protease Using Molecular Docking and Molecular Dynamics Simulations

Indonesian Journal of Chemistry ◽

10.22146/ijc.65951 ◽

2021 ◽

Vol 21 (5) ◽

pp. 1252

Author(s):

Ari Hardianto ◽

Muhammad Yusuf ◽

Ika Wiani Hidayat ◽

Safri Ishmayana ◽

Ukun Mochammad Syukur Soedjanaatmadja

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulations ◽

Global Economy ◽

Nigella Sativa ◽

Scientific Information ◽

Dynamics Simulation ◽

Lipinski’S Rule ◽

Main Protease ◽

Dynamics Simulations

Coronavirus disease (COVID-19) is a pandemic burdening the global economy. It is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Black cumin (Nigella sativa) seed may contain antivirals for the disease since it was reported to inhibit the human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Main protease (Mpro) is a vital protein for viral replication and a promising target for COVID-19 drug development. Hence, in this study, we intended to uncover the potency of N. sativa seed as the natural source of inhibitors for SARS-CoV-2 Mpro. We collected secondary metabolites in N. sativa seed through a literature search and employed Lipinski’s rule of five as the initial filter. Subsequently, virtual screening campaigns using a molecular docking method were performed, with N3 inhibitor and leupeptin as reference ligands. The top hits were analyzed further using a molecular dynamics simulation approach. Molecular dynamics simulations showed that binding affinities of nigellamine A2 and A3 to Mpro are comparable to that of leupeptin, with median values of -43.9 and -36.2 kcal mol–1, respectively. Ultimately, this study provides scientific information regarding N. sativa seeds’ potency against COVID-19 and helps direct further wet experiments.

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Computational analysis by molecular docking of thirty alkaloid compounds from medicinal plants as potent inhibitors of SARS-CoV-2 main protease

10.21203/rs.3.rs-94752/v1 ◽

2020 ◽

Author(s):

Tunga Kuhana A. ◽

Jason T. Kilembe ◽

Aristote Matondo ◽

Khamis M. Yussuf ◽

Lauraine Nininahazwe ◽

...

Keyword(s):

Molecular Docking ◽

Medicinal Plants ◽

Computational Analysis ◽

Binding Energies ◽

Effective Drug ◽

Potential Drug ◽

Lipinski’S Rule ◽

Main Protease ◽

Lipinski’S Rule Of Five ◽

Potential Inhibitors

Abstract 2020 has been highly affected by the COVID-19 outbreak. The urgent needs for a potent and effective drug for treatment of this malignance put pressure on researchers and scientists worldwide to develop potential drug or a vaccine to resist SARS-CoV-2. We report in this paper the assessment of the efficiency of thirty alkaloid compounds derived from African medicinal plants against the SARS-CoV-2 main protease through molecular docking and bioinformatics approaches. The results reveal four potential inhibitors (ligands 18, 21, 23 and 24) with the highest binding energies up to 12.26 kcal/mol with good profile of ADMET, as well as fully obey the Lipinski’s rule of five.

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Inhibition Potencies of Phytochemicals Derived from Sesame Against SARS-CoV-2 Main Protease: A Molecular Docking and Simulation Study

Frontiers in Chemistry ◽

10.3389/fchem.2021.744376 ◽

2021 ◽

Vol 9 ◽

Author(s):

Anuj Kumar ◽

Dwijesh Chandra Mishra ◽

Ulavappa Basavanneppa Angadi ◽

Rashmi Yadav ◽

Anil Rai ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Drug Targets ◽

Human Life ◽

Md Simulations ◽

Natural Compounds ◽

Free Energy Calculations ◽

Lipinski’S Rule ◽

Protease Enzyme ◽

Main Protease

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, has now spread across the nations with high mortality rates and multifaceted impact on human life. The proper treatment methods to overcome this contagious disease are still limited. The main protease enzyme (Mpro, also called 3CLpro) is essential for viral replication and has been considered as one of the potent drug targets for treating COVID-19. In this study, virtual screening was performed to find out the molecular interactions between 36 natural compounds derived from sesame and the Mpro of COVID-19. Four natural metabolites, namely, sesamin, sesaminol, sesamolin, and sesamolinol have been ranked as the top interacting molecules to Mpro based on the affinity of molecular docking. Moreover, stability of these four sesame-specific natural compounds has also been evaluated using molecular dynamics (MD) simulations for 200 nanoseconds. The molecular dynamics simulations and free energy calculations revealed that these compounds have stable and favorable energies, causing strong binding with Mpro. These screened natural metabolites also meet the essential conditions for drug likeness such as absorption, distribution, metabolism, and excretion (ADME) properties as well as Lipinski’s rule of five. Our finding suggests that these screened natural compounds may be evolved as promising therapeutics against COVID-19.

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