Identification of Natural Compounds (Proanthocyanidin and Rhapontin) as High-Affinity Inhibitor of SARS-CoV-2 Mpro and PLpro using Computational Strategies

IntroductionThe emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic loss. Amongst many proteins encoded by SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and Papain-like protease (PLpro) serve as an attractive drug target.Material and methodsWe screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). 50 top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal mol-1 against Mpro and ≤ -5.0 kcal mol-1 against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes.ResultsProanthocyanidin and Rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while Rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of Proanthocyanidin and Rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol.ConclusionsThis study's outcome may serve Proanthocyanidin and Rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validations by in vitro and in vivo studies.

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Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

Applied Biological Chemistry ◽

10.1186/s13765-020-00564-4 ◽

2020 ◽

Vol 63 (1) ◽

Author(s):

Ghazala Muteeb ◽

Adil Alshoaibi ◽

Mohammad Aatif ◽

Md. Tabish Rehman ◽

M. Zuhaib Qayyum

Keyword(s):

Hydrophobic Interactions ◽

In Silico Analysis ◽

Salt Bridge ◽

Competitive Inhibitor ◽

Binding Energies ◽

Dynamics Simulation ◽

In Vivo Studies ◽

Energy Calculation

AbstractThe recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score < − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

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THE POTENTIAL OF ROBUSTA COFFEE (COFFEA CANEPHORA) AS A COLORECTAL CANCER THERAPY MODALITY: AN IN SILICO STUDY

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2021.v14i10.43025 ◽

2021 ◽

pp. 83-87

Author(s):

DESSY AGUSTINI ◽

LEO VERNADESLY ◽

DELVIANA ◽

THEODORUS

Keyword(s):

Colorectal Cancer ◽

In Silico ◽

Hydrophobic Interactions ◽

Binding Energies ◽

In Vivo Studies ◽

Discovery Studio ◽

Robusta Coffee ◽

In Silico Study

Objectives: This research aims to determine the efficacy of compounds in robusta coffee against colorectal cancer through the inhibition of the T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) receptor. Methods: This in silico study has been conducted in computing platform from June to August 2021. The selected test compounds would go through the Lipinski rule screening through the SwissADME website and the compounds that met these regulations would be docked to the TIGIT protein using AutoDock Tools and AutoDock Vina. The interactions with the highest binding energies were visualized using BIOVIA Discovery Studio 2020. The test compounds then underwent a toxicity profile analysis on the admetSAR 2.0 website. Results: All test compounds complied with the Lipinski rule. The molecular docking results showed the highest binding energy in kahweol and cafestol (−8.1 kcal/mol) compared to OMC (−7.9 kcal/mol), chlorogenic acid (−7.8 kcal/mol), caffeic acid (−6.3 kcal/mol), caffeine (−6.1 kcal/mol), trigonelline (−5.3 kcal/mol), HMF (−5.1 kcal/mol), furfuryl alcohol (−4.4 kcal/mol), and 5-fluorouracil as the comparator drug (−5.3 kcal/mol). Kahweol, cafestol, and 5-fluorouracil revealed the hydrophobic interactions and hydrogen bonds with amino acid residues in TIGIT. Kahweol and cafestol unveiled minimal toxicity prediction Conclusion: Kahweol and cafestol demonstrated the best results in inhibiting the TIGIT protein which played a role in colorectal cancer. In vitro and in vivo studies are needed to strengthen the findings of this research.

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Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

10.26434/chemrxiv.12362333.v2 ◽

2020 ◽

Cited By ~ 4

Author(s):

Md Tabish Rehman ◽

Mohamed F AlAjmi ◽

Afzal Hussain

Keyword(s):

Clinical Trials ◽

Hydrophobic Interactions ◽

Rapid Development ◽

Economic Loss ◽

Binding Pocket ◽

Natural Compounds ◽

Active Site Residues ◽

Reference Drug ◽

Drug Molecules ◽

Main Protease

Recently, the emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. In the fight against COVID-19, the rapid development of new drug molecules is the need of hour. However, the conventional approaches of drug development is time consuming and expensive in nature. In this study, we have adopted an alternative approach to identify lead molecules from natural sources using high throughput virtual screening approach. Ligands from natural compounds library from Selleck Inc (L1400) have been screened to evaluate their ability to bind and inhibit the main protease (Mpro or 3CLpro) of SARS-CoV-2, which is a potential drug target. We found that Kaempferol, Quercetin, and Rutin were able to bind at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin was much higher than Chloroquine (1000 times) and Hydroxychloroquine (100 times) and was comparable to that of the reference drug Remdesivir, which is in clinical trials to treat COVID-19 patients. The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.

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Fragment-Based Virtual Screening to Discover Potential Plasmodium PI4KIIIβ Ligands

10.20944/preprints202111.0108.v1 ◽

2021 ◽

Author(s):

Akachukwu Ibezim ◽

Mbanefo S. Madukaife ◽

Sochi C Osigwe ◽

Nadja Engel ◽

Ramanathan Karuppasamy ◽

...

Keyword(s):

Antimalarial Activity ◽

Plasmodium Species ◽

Homology Model ◽

Binding Energies ◽

Dynamics Simulation ◽

Active Site Residues ◽

Starting Point ◽

Binding Cavity

Plasmodium species that cause malaria, a disease responsible for about half a million deaths per annum despite concerted efforts to combat it. The causative agent depends on type III beta phosphatidylinositol 4-kinase (PPI4K) during the development of merozoite. PPI4K is the only clinically validated Plasmodium kinase so far and its inhibitors are effective both in vitro and in vivo. In this work, a small library of ~22 000 fragments was virtually screened using PPI4K homology model to discover potential ligands of the enzyme. 16 virtual hits were selected based on ≤ -9.0 kcal/mol binding energy cut off and were subjected to similarity and substructure searching after they had passed PAINS screening. The derivatives obtained showed improved binding energies, which ranged from -10.00 to -13.80 kcal/mol. Moreover, the topmost ranking compound 31, with interesting drug-like quality was stable within the protein’s binding cavity during the 10 ns molecular dynamics simulation period. In addition, analysis of its binding pose revealed some unique binding interactions with PPI4K active site residues as the basis for the observed improved binding affinity. Overall, compound 31 appears to be a viable starting point for the development of PPI4K inhibitors with antimalarial activity.

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The Role of Selected Natural Biomolecules in Sperm Production and Functionality

Molecules ◽

10.3390/molecules26175196 ◽

2021 ◽

Vol 26 (17) ◽

pp. 5196

Author(s):

Eva Tvrdá ◽

Filip Benko ◽

Tomáš Slanina ◽

Stefan S. du Plessis

Keyword(s):

Molecular Mechanisms ◽

Structural Integrity ◽

Biological Effects ◽

Natural Compounds ◽

In Vivo Studies ◽

Dna Integrity ◽

Sperm Production ◽

Reproductive Dysfunction

Emerging evidence from in vivo as well as in vitro studies indicates that natural biomolecules may play important roles in the prevention or management of a wide array of chronic diseases. Furthermore, the use of natural compounds in the treatment of male sub- or infertility has been proposed as a potential alternative to conventional therapeutic options. As such, we aimed to evaluate the effects of selected natural biomolecules on the sperm production, structural integrity, and functional activity. At the same time, we reviewed their possible beneficial or adverse effects on male reproductive health. Using relevant keywords, a literature search was performed to collect currently available information regarding molecular mechanisms by which selected natural biomolecules exhibit their biological effects in the context of male reproductive dysfunction. Evidence gathered from clinical trials, in vitro experiments and in vivo studies suggest that the selected natural compounds affect key targets related to sperm mitochondrial metabolism and motion behavior, oxidative stress, inflammation, DNA integrity and cell death. The majority of reports emphasize on ameliorative, stimulating and protective effects of natural biomolecules on the sperm function. Nevertheless, possible adverse and toxic behavior of natural compounds has been indicated as well, pointing out to a possible dose-dependent impact of natural biomolecules on the sperm survival and functionality. As such, further research leading to a deeper understanding of the beneficial or adverse roles of natural compounds is necessary before these can be employed for the management of male reproductive dysfunction.

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Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

10.26434/chemrxiv.12362333.v1 ◽

2020 ◽

Author(s):

Md Tabish Rehman ◽

Mohamed F AlAjmi ◽

Afzal Hussain

Keyword(s):

Hydrophobic Interactions ◽

Rapid Development ◽

Economic Loss ◽

Binding Pocket ◽

Natural Compounds ◽

Active Site Residues ◽

Reference Drug ◽

Drug Molecules ◽

Main Protease ◽

Alternative Approach

Recently, the emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. In the fight against COVID-19, the rapid development of new drug molecules is the need of hour. However, the conventional approaches of drug development is time consuming and costly in nature. In this study, we have adopted an alternative approach to identify lead molecules from natural sources using high throughput virtual screening approach. Ligands from natural compounds library from Selleck Inc (L1400) have been screened to evaluate their ability to bind and inhibit the main protease (Mpro or 3CLpro) of SARS-CoV-2, which is a potential drug target. We found that Kaempferol, Quercetin, and Rutin were able to bind at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin was much higher than Chloroquine (1000 times) and Hydroxychloroquine (100 times) and was comparable to that of the reference drug Remdesivir, which is in clinical trials to treat COVID-19 patients. The results suggest the potential of natural compounds (flavonoids) as novel inhibitors of SARS-CoV-2 with comparable potency as that of Remdesivir.

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The Potential of Serratiopetidase and Lumbrokinase for the Degradation of Prion Peptide 106-126 - an In Vitro and In Silico Perspective

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666191021150002 ◽

2020 ◽

Vol 18 (9) ◽

pp. 723-731

Author(s):

Sanjay Kisan Metkar ◽

Suparna Ghosh ◽

Agnishwar Girigoswami ◽

Koyeli Girigoswami

Keyword(s):

Cell Viability ◽

Serine Proteases ◽

Prion Diseases ◽

Dynamics Simulation ◽

In Vivo Studies ◽

Drug Candidate ◽

Amyloid Formation ◽

Β Sheet

Background: PrPC is a host-encoded prion protein, which gets post translationally modified into a transmissible, β-sheet rich disease associated protein called PrPSc, responsible for the Prion disease including mad cow disease in cattle and CJD in humans. The PrP 106-126 region in PrPSc peptide initiates the conformational change in that protein leading to fibrillation. Any agent that can destabilize or disintegrate such proteins can be served as a potential drug candidate for Prion diseases. Methods: In the present study, an enzyme Lumbrokinase (LK) was isolated from earthworm and its activity was exploited towards PrP 106-126 amyloids in vitro along with another enzyme Serratiopeptidase (SP) taking Nattokinase (NK) as a standard. Results: The results showed that PrP 106-126 amyloid formation was inhibited by both LK and SP, as evidenced from Thioflavin T fluorescence assay. Further, the size of fibrils as estimated by dynamic light scattering, was also found to be lower at different time intervals after incubation of the prion amyloids with LK and SP. Additionally, the molecular dynamics simulation revealed the thermodynamically favorable interaction of PrP 106-126 with LK as well as with SP with high affinity. Conclusion: Finally, the toxicity of the disintegrated amyloids was assessed using PC12 cell lines which showed higher cell viability in case of LK and SP treated amyloids compared to only PrP 106- 126 amyloid treatment. Altogether, the study concluded that the serine proteases like LK and SP have the potential to disintegrate PrP 106-126 amyloids with improved cell viability. The in vivo studies are needed to be executed in future.

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In-Silico Evaluation of Tiryaq-E-Wabai, an Unani Formulation for its Potency against SARS-CoV-2 Spike Glycoprotein and Main Protease

Journal of Drug Delivery and Therapeutics ◽

10.22270/jddt.v11i4-s.4993 ◽

2021 ◽

Vol 11 (4-S) ◽

pp. 86-100

Author(s):

N ZAHEER AHMED ◽

DICKY JOHN DAVIS ◽

NOMAN ANWAR ◽

ASIM ALI KHAN ◽

RAM PRATAP MEENA ◽

...

Keyword(s):

In Silico ◽

Dynamics Simulation ◽

In Vivo Studies ◽

Spike Glycoprotein ◽

Unani Medicine ◽

Main Protease ◽

Pubchem Database ◽

The Stability

COVID-19 was originated in Wuhan, China, in December 2019 and has been declared a pandemic disease by WHO. The number of infected cases continues unabated and so far, no specific drug approved for targeted therapy. Hence, there is a need for drug discovery from traditional medicine. Tiryaq-e-Wabai is a well-documented formulation in Unani medicine for its wide use as prophylaxis during epidemics of cholera, plague and other earlier epidemic diseases. The objective of the current study is to generate in-silico evidence and evaluate the potency of Tiryaq-e-Wabai against SARS-CoV-2 spike (S) glycoprotein and main protease (3CLpro). The structures of all phytocompounds used in this study were retrieved from PubChem database and some were built using Marvin Sketch. The protein structure of the SARS-CoV-2 S glycoprotein and 3CLpro was retrieved from the PDB ID: 6LZG and 7BQY respectively. AutoDock Vina was used to predict top ranking poses with best scores. The results of the molecular docking showed that phytocompounds of Tiryaq-e-Wabai exhibited good docking power with spike glycoprotein and 3CLpro. Among tested compounds Crocin from Zafran and Aloin A from Sibr showed strong binding to spike glycoprotein and 3CLpro respectively. Molecular dynamics simulation confirmed the stability of the S glycoprotein-Crocin and 3CLpro-Aloin A complexes. The Unani formulation Tiryaq-e-Wabai has great potential to inhibit the SARS-CoV-2, which have to be substantiated with further in-vitro and in-vivo studies. Keywords: In-silico study, SARS-CoV-2, Tiryaq-e-Wabai, Unani formulation, Crocin, Aloin A

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Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)

Molecules ◽

10.3390/molecules25102271 ◽

2020 ◽

Vol 25 (10) ◽

pp. 2271 ◽

Cited By ~ 21

Author(s):

Noor Rahman ◽

Zarrin Basharat ◽

Muhammad Yousuf ◽

Giuseppe Castaldo ◽

Luca Rastrelli ◽

...

Keyword(s):

Molecular Docking ◽

Three Dimensional ◽

Natural Compounds ◽

Structural Features ◽

Host Cells ◽

Dimensional Structure ◽

Active Site Residues ◽

Transmembrane Serine Protease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused about 2 million infections and is responsible for more than 100,000 deaths worldwide. To date, there is no specific drug registered to combat the disease it causes, named coronavirus disease 2019 (COVID-19). In the current study, we used an in silico approach to screen natural compounds to find potent inhibitors of the host enzyme transmembrane protease serine 2 (TMPRSS2). This enzyme facilitates viral particle entry into host cells, and its inhibition blocks virus fusion with angiotensin-converting enzyme 2 (ACE2). This, in turn, restricts SARS-CoV-2 pathogenesis. A three-dimensional structure of TMPRSS2 was built using SWISS-MODEL and validated by RAMPAGE. The natural compounds library Natural Product Activity and Species Source (NPASS), containing 30,927 compounds, was screened against the target protein. Two techniques were used in the Molecular Operating Environment (MOE) for this purpose, i.e., a ligand-based pharmacophore approach and a molecular docking-based screening. In total, 2140 compounds with pharmacophoric features were retained using the first approach. Using the second approach, 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied for physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2, with a binding energy score of −14.69. Further in vitro and in vivo validation is needed to study and develop an anti-COVID-19 drug based on the structures of the most promising compounds identified in this study.

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Fluctuations of Histone Chemical Modifications in Breast, Prostate, and Colorectal Cancer: An Implication of Phytochemicals as Defenders of Chromatin Equilibrium

Biomolecules ◽

10.3390/biom9120829 ◽

2019 ◽

Vol 9 (12) ◽

pp. 829 ◽

Cited By ~ 5

Author(s):

Marek Samec ◽

Alena Liskova ◽

Lenka Koklesova ◽

Veronika Mestanova ◽

Maria Franekova ◽

...

Keyword(s):

Cancer Research ◽

Chromatin Structure ◽

Natural Compounds ◽

In Vivo Studies ◽

Regulation Of Transcription ◽

Natural Substances ◽

Incidence And Mortality ◽

Posttranslational Histone Modifications

Natural substances of plant origin exert health beneficiary efficacy due to the content of various phytochemicals. Significant anticancer abilities of natural compounds are mediated via various processes such as regulation of a cell’s epigenome. The potential antineoplastic activity of plant natural substances mediated by their action on posttranslational histone modifications (PHMs) is currently a highly evaluated area of cancer research. PHMs play an important role in maintaining chromatin structure and regulating gene expression. Aberrations in PHMs are directly linked to the process of carcinogenesis in cancer such as breast (BC), prostate (PC), and colorectal (CRC) cancer, common malignant diseases in terms of incidence and mortality among both men and women. This review summarizes the effects of plant phytochemicals (isolated or mixtures) on cancer-associated PHMs (mainly modulation of acetylation and methylation) resulting in alterations of chromatin structure that are related to the regulation of transcription activity of specific oncogenes, which are crucial in the development of BC, PC, and CRC. Significant effectiveness of natural compounds in the modulation of aberrant PHMs were confirmed by a number of in vitro or in vivo studies in preclinical cancer research. However, evidence concerning PHMs-modulating abilities of plant-based natural substances in clinical trials is insufficient.

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