Molecular Docking Strategy for Multi-Target Inhibitor Discovery of Selected Plant Constituents in Bauhinia Acuminata

Objective: Traditional medicine is often considered to be a kind of complementary or alternative medicine (CAM) nowadays. Therefore, documenting and identifying the herbs that are effective in treating various diseases is vital for future disease control programs. This study aims to perform a molecular docking analysis of the thirteen plant components in Bauhinia acuminata against the target proteins in lung cancer (PDB IDs: 2ITY), breast cancer (1A52), diabetes (3L4U), obesity (IT02), inflammation (5COX) and corona viral infections (6VYO). Material(s) and Method(s): All the plant components used for the present study were retrieved from the plant Bauhinia acuminata and were evaluated for their biological activity results using molinspiration. Further in-silico docking analysis was performed using AutoDock Vina software and the binding interactions were visualized using Discovery studio program. Result and Discussion: The docking scores and analysis of the interactions of the plant components with targets suggest that all the selected plant components showed excellent binding to the chosen targets when compared to that of the standard drugs. As a result of the docking process on 6 different targets, the selected plant components like Quercetin, Beta-sitosterol, and Rheagenine were observed to show good binding energy values against all the 5 targets except 6VYO as shown in (Table 9). These results can further pave the way for getting better insights in identifying and designing potential lead candidates.Copyright © 2022 University of Ankara. All rights reserved.

Computational Interaction Study of Immunomodulatory Plant Derivatives Against SARS-Cov-2 Mpro Target

The COVID-19 pandemic has been reported to have a high incidence of morbidity and mortality, resulting in a large number of human deaths over the world. Studies suggest the importance of natural phytocompounds as potential antiviral agents and hypothesize to use them as therapeutics against COVID-19 main protease target. This study aims to identify a therapeutically potential natural compound from the immunomodulatory plants to inhibit the progression of the SARS CoV-2 virus. A total 8 major constituents, from various immunomodulatory-medicinal plants used in ayurvedic kadha preparation i.e. Cinnamon species (Dalchini), Piper nigrum (Kaali Mirch), Ocimum tenuiflorum (Tulsi), Zingiber officinale (Ginger), and Withania somnifera (Ashwagandha), have been used to perform docking with drug target main protease structure (SARS-CoV-2 Mpro, PDB ID: 6LU7) followed by molecular simulations. The pharmacological evaluations such as drug likeliness and ADMET properties calculations and RMSD calculation for 50 ns time scale of molecular dynamics support the current investigation. This study provides evidence of comparative significance with possible computational validations for Withaferin A of W. somnifera (Ashwagandha) with therapeutic potential towards SARS-CoV-2 Mpro, as a lead molecule. This chapter shows the different properties of natural phytocompounds, which are available in ayurvedic kadha as described by the government of India. Further, it details about different computational softwares/pipelines (off lines/online, Free/commercial) used for molecular docking and dynamics analysis. The chapter explains all the associated steps/execution of programs with a demonstration of the antiviral capacity of the phytocompounds from immunomodulatory plants through the case study. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022.

In Silico Screening of Some Anti-Cancer Drugs Against the Main Protease of COVID-19 Using Molecular Docking

The SARS-CoV-2 pandemic has led to major worldwide health concerns. Design and detection of effective drugs and adjuvant therapies to treat COVID-19 disease in the shortest possible time have become one of the most critical global challenges. In this study, we investigated the effect of some anticancer drugs against the COVID-19 main protease (Mpro/3CLpro) to detect an effective treat-ment, using a molecular docking approach as a fast and cost-effective method. Accordingly, 44 anti-cancer drugs were selected as a target for the virtual screening. The molecular docking study was car-ried out using AutoDock Tools (ADT), AutoDock Vina, Discovery Studio, and Open Babel software. Tucatinib, selinexor, irinotecan, olaparib, dacomitinib, lapatinib, ibrutinib, and pazopanib were ranked top as COVID-19 inhibitors with the respective binding energy of-10.1,-9.4,-9.2,-8.9,-8.7,-8.7,-8.6, and-8.5 kcal/mol. Among the drugs tested, tucatinib displayed the highest binding affinity and strong interactions with the active site of COVID-19 3CLpro (-10.1 kcal/mol). Pharmacokinetics properties and drug-likeness of the top 8 selected anticancer drugs were evaluated. The results showed that these drugs could be utilized as potential inhibitors against the main protease of COVID-19, which can help control the spread of this disease. However, in vitro, in vivo studies, and clinical trials will help evalu-ate the efficacy of these drugs against COVID-19. © 2023 Bentham Science Publishers.

In Silico Screening of Plant-Derived Anti-virals from Shorea hemsleyana (King) King ex Foxw Against SARS CoV-2 Main Protease

Shorea hemsleyana (King) King ex Foxw is used to treat various ailments in humans. Numerous biological activities have been reported previously. The current study sought to identify S. hemsleyana phyto-derived anti-viral compounds against the SARS-CoV-2 main protease to gain insight into the molecular interactions. In the present research, nine compounds obtained from the PubChem database are examined via molecular docking. Docking experiments were conducted using the AutoDock Vina tool. The Swiss ADME and DruLito servers were used for drug-like predictions. Our research shows that the phytoconstituents of S. hemsleyana, namely, Hemsleyanol-A and Hemsleyanoside-A, may act against SARS CoV-2 main protease with the binding affinity of - 7.6 and - 6.8 kcal/mol respectively, which were further validated by molecular dynamics (MD) simulations and end-state binding energy calculations. These phytocompounds could be used in contemporary strategies to develop effective medicines from natural sources. The identified substances are potential anti-viral agents. However, in vitro studies are necessary to assess their effectiveness against SARS-CoV-2.

Benchmarked molecular docking integrated molecular dynamics stability analysis for prediction of SARS-CoV-2 papain-like protease inhibition by olive secoiridoids.

Objectives: We performed a virtual screening of olive secoiridoids of the OliveNetTM library to predict SARS-CoV-2 PLpro inhibition. Benchmarked molecular docking protocol that evaluated the performance of two docking programs was applied to execute virtual screening. Molecular dynamics stability analysis of the top-ranked olive secoiridoid docked to PLpro was also carried out. Methods: Benchmarking virtual screening used two freely available docking programs, AutoDock Vina 1.1.2. and AutoDock 4.2.1. for molecular docking of olive secoiridoids to a single PLpro structure. Screening also included benchmark structures of known active and decoy molecules from the DEKOIS 2.0 library. Based on the predicted binding energies, the docking programs ranked the screened molecules. We applied the usual performance evaluation metrices to evaluate the docking programs using the predicted ranks. Molecular dynamics of the top-ranked olive secoiridoid bound to PLpro and computation of MM-GBSA energy using three iterations during the last 50 ps of the analysis of the dynamics in Desmond supported the stability prediction. Results and discussions: Predictiveness curves suggested that AutoDock Vina has a better predictive ability than AutoDock, although there was a moderate correlation between the active molecules rankings (Kendall's correlation of rank (τ) = 0.581). Interestingly, two same molecules, Demethyloleuropein aglycone, and Oleuroside enriched the top 1 % ranked olive secoiridoids predicted by both programs. Demethyloleuropein aglycone bound to PLpro obtained by docking in AutoDock Vina when analyzed for stability by molecular dynamics simulation for 50 ns displayed an RMSD, RMSF<2 Å, and MM-GBSA energy of -94.54 ± 6.05 kcal/mol indicating good stability. Molecular dynamics also revealed the interactions of Demethyloleuropein aglycone with binding sites 2 and 3 of PLpro, suggesting a potent inhibition. In addition, for 98 % of the simulation time, two phenolic hydroxy groups of Demethyloleuropein aglycone maintained two hydrogen bonds with Asp302 of PLpro, specifying the significance of the groups in receptor binding. Conclusion: AutoDock Vina retrieved the active molecules accurately and predicted Demethyloleuropein aglycone as the best inhibitor of PLpro. The Arabian diet consisting of olive products rich in secoiridoids benefits from the PLpro inhibition property and reduces the risk of viral infection.

Methylxanthines as Potential Inhibitor of SARS-CoV-2: an In Silico Approach.

The aim of the present study was to test the binding affinity of methylxanthines (caffeine/theine, methylxanthine, theobromine, theophylline and xanthine) to three potential target proteins namely Spike protein (6LZG), main protease (6LU7) and nucleocapsid protein N-terminal RNA binding domain (6M3M) of SARS-CoV-2. Proteins and ligand were generated using AutoDock 1.5.6 software. Binding affinity of methylxanthines with SARS-CoV-2 target proteins was determined using Autodock Vina. MD simulation of the best interacting complexes was performed using GROMACS 2018.3 (in duplicate) and Desmond program version 2.0 (academic version) (in triplicate) to study the stabile interaction of protein-ligand complexes. Among the selected methylxanthines, theophylline showed the best binding affinity with all the three targets of SARS-CoV-2 (6LZG - 5.7 kcal mol-1, 6LU7 - 6.5 kcal mol-1, 6M3M - 5.8 kcal mol-1). MD simulation results of 100 ns (in triplicate) showed that theophylline is stable in the binding pockets of all the selected SARS-CoV-2 proteins. Moreover, methylxanthines are safer and less toxic as shown by high LD50 value with Protox II software as compared to drug chloroquine. This research supports the use of methylxanthines as a SARS-CoV-2 inhibitor. It also lays the groundwork for future studies and could aid in the development of a treatment for SARS-CoV-2 and related viral infections. Supplementary Information: The online version contains supplementary material available at 10.1007/s40495-021-00276-3.

Virtual screening, drug-likeness analysis, and molecular docking study of potential severe acute respiratory syndrome coronavirus 2 main protease inhibitors

Due to the length of time required to develop specific antiviral agents, the World Health Organization adopted the strategy of repurposing existing medications to treat Coronavirus disease 2019 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease is possible biological target for potential antiviral drugs. We selected various compounds from PubChem database based on the structure of main protease inhibitors in Protein Data Bank database. Ten compounds showed nontumorigenic and nonmutagenic potential and met Egan's and Lipinski's rules. Molecular docking analysis was performed using AutoDock Vina software. Based on number and type of key binding interactions, as well as docking scores, we selected compounds 6, 8, and 17 that demonstrated the highest binding affinity for the target protein. Molecular dynamics simulations were then carried out on the protein-top docked ligand complexes which were subjected to Molecular mechanics/generalized Born and surface area calculations. The molecular dynamics simulation results indicated that protein-top docked ligand complexes showed good conformational stability. Among analyzed molecules, compound 17 emerged as the best in silico hit based on the docking score, MM/GBSA binding energy and MD results.

Virtual screening on the web for drug repurposing: a primer.

We describe a procedure of performing in silico (virtual) screening using a web-based service, the MTiOpenScreen, which is freely accessible to non-commercial users. We shall use the SARS-CoV-2 main protease as an example. Starting from a structure downloaded from the Protein Data Bank, we discuss how to prepare the coordinates file, taking into account the known biochemical background information of the target protein. The reader will find that this preparation step takes up most of the effort before the target is ready for screening. The steps for uploading the target structure and defining the search volume by critical residues, and the main parameters to use, are outlined. When this protocol is followed, the user will expect to obtain a ranked list of small approved drug compounds docked into the target structure. The results can be readily examined graphically on the web site or downloaded for studying in a local molecular graphics program such as PyMOL.

Molecular Human Targets of Bioactive Alkaloid-Type Compounds from Tabernaemontana cymose Jacq.

Alkaloids are a group of secondary metabolites that have been widely studied for the discovery of new drugs due to their properties on the central nervous system and their anti-inflammatory, antioxidant and anti-cancer activities. Molecular docking was performed for 10 indole alkaloids identified in the ethanol extract of Tabernaemontana cymosa Jacq. with 951 human targets involved in different diseases. The results were analyzed through the KEGG and STRING databases, finding the most relevant physiological associations for alkaloids. The molecule 5-oxocoronaridine proved to be the most active molecule against human proteins (binding energy affinity average = -9.2 kcal/mol) and the analysis of the interactions between the affected proteins pointed to the PI3K/ Akt/mTOR signaling pathway as the main target. The above indicates that indole alkaloids from T. cymosa constitute a promising source for the search and development of new treatments against different types of cancer.

Structure-based virtual screening of bioactive compounds from Indonesian medical plants against severe acute respiratory syndrome coronavirus-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a virus that causes the infectious disease coronavirus disease-2019. Currently, there is no effective drug for the prevention and treatment of this virus. This study aimed to identify secondary metabolites that potentially inhibit the key proteins of SARS-CoV-2. This was an in silico molecular docking study of several secondary metabolites of Indonesian herbal plant compounds and other metabolites with antiviral testing history. Virtual screening using AutoDock Vina of 216 Lipinski rule-compliant plant metabolites was performed on 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), and spike glycoprotein. Ligand preparation was performed using JChem and Schrödinger's software, and virtual protein elucidation was performed using AutoDockTools version 1.5.6. Virtual screening identified several RdRp, spike, and 3CLpro inhibitors. Justicidin D had binding affinities of -8.7, -8.1, and -7.6 kcal mol-1 on RdRp, 3CLpro, and spike, respectively. 10-methoxycamptothecin had binding affinities of -8.5 and -8.2 kcal mol-1 on RdRp and spike, respectively. Inoxanthone had binding affinities of -8.3 and -8.1 kcal mol-1 on RdRp and spike, respectively, while binding affinities of caribine were -9.0 and -7.5 mol-1 on 3CLpro and spike, respectively. Secondary metabolites of compounds from several plants were identified as potential agents for SARS-CoV-2 therapy.

Direct acting anti-hepatitis C combinations as potential COVID-19 protease inhibitors.

The coronavirus pandemic could be the most threatening outbreak in the twenty-first century. According to the latest records of world health organization, more than 130 millions have been infected by COVID-19, with more than 2.9 million reported deaths. Yet, there is no magic cure for treatment of COVID-19. The concept of drug repurposing has been introduced as a fast, life-saving approach for drug discovery. Drug repurposing infers investigating already approved drugs for new indications, using the available information about pathophysiology of diseases and pharmacodynamics of drugs. In a recent work, more than 3000 FDA approved drugs were tested using virtual screening as potential antiviral agents for COVID-19. In this work, the top ranked five hits from the previous docking results together with drugs of similar chemical feature and/or mechanistic destinations were further tested using AutoDock Vina. The results showed that anti-HCV combinations could be potential therapeutic regimens for COVID-19 infections. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13337-021-00691-6.

Structure-based drug design of an inhibitor of the SARS-CoV-2 (COVID-19) main protease using free software: A tutorial for students and scientists.

This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (Mpro) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the Mpro active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV Mpro and the highly homologous SARS-CoV-2 Mpro. The supporting information provides an illustrated step-by-step protocol, as well as a video showing the inhibitor design process, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [https://doi.org/10.1101/2020.08.03.234872] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 Mpro.

Screening of plant-based natural compounds as a potential COVID-19 main protease inhibitor: an in silico docking and molecular dynamics simulation approach.

A new strain of coronavirus (CoV) has been identified as SARS-CoV-2, which is responsible for the recent COVID-19 pandemic. Currently, there is no approved vaccine or drug available to combat the pandemic. COVID-19 main protease (Mpro) is a key CoV enzyme, which plays an important role in triggering viral replication and transcription, turns it into an attractive target. Therefore, we aim to screen natural products library to find out potential COVID-19 Mpro inhibitors. Plant-based natural compounds from Sigma-Aldrich plant profiler chemical library have been screened through virtual molecular docking and molecular dynamics simulation to identify potential inhibitors of COVID Mpro. Our virtual molecular docking results have shown that there are twenty-eight natural compounds with a greater binding affinity toward the COVID-19 Mpro inhibition site as compared to the co-crystal native ligand Inhibitor N3 (-7.9 kcal/mol). Also, molecular dynamics simulation results have confirmed that Peonidin 3-O-glucoside, Kaempferol 3-O-ß-rutinoside, 4-(3,4-Dihydroxyphenyl)-7-methoxy-5-[(6-O-ß-D-xylopyranosyl-ß-D-glucopyranosyl)oxy]-2H-1-benzopyran-2-one, Quercetin-3-D-xyloside, and Quercetin 3-O-α-L-arabinopyranoside (selected based on the docking score) possess a significant amount of dynamic properties such as stability, flexibility and binding energy. Our In silco results suggests that all the above mention natural compounds have the potential to be developed as a COVID-19 Mpro inhibitor. But before that, it must go through under the proper preclinical and clinical trials for further scientific validation.Communicated by Ramaswamy H. Sarma.

nCOV-19 peptides mass fingerprinting identification, binding, and blocking of inhibitors flavonoids and anthraquinone of Moringa oleifera and hydroxychloroquine.

An rare pandemic of viral pneumonia occurs in December 2019 in Wuhan, China, which is now recognized internationally as Corona Virus Disease 2019 (COVID-19), the etiological agent classified as Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). According to the World Health Organization (WHO), it has so far expanded to more than 213 countries/territories worldwide. Our study aims to find the viral peptides of SARS-COV-2 by peptide mass fingerprinting (PMF) in order to predict its novel structure and find an inhibitor for each viral peptide. For this reason, we calculated the mass of amino acid sequences translated from the SARS-CoV2 whole genome and identify the peptides that may be a target for inhibition. Molecular peptide docking with Moringa oleifera, phytochemicals (aqueous and ethanolic) leaf extracts of flavonoids (3.56 ± 0.03), (3.83 ± 0.02), anthraquinone (11.68 ± 0.04), (10.86 ± 0.06) and hydroxychloroquine present therapy of COVID-19 in Pakistan for comparative study. Results indicate that 15 peptides of SARS-CoV2 have been identified from PMF, which is then used as a selective inhibitor. The maximum energy obtained from AutoDock Vina for hydroxychloroquine is -5.1 kcal/mol, kaempferol (flavonoid) is -6.2 kcal/mol, and for anthraquinone -6 kcal/mol. Visualization of docking complex, important effects are observed regarding the binding of peptides to drug compounds. In conclusion, it is proposed that these compounds are effective antiviral agents against COVID-19 and can be used in clinical trials.Communicated by Ramaswamy H. Sarma.

Computational screening of antagonists against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking.

In the current spread of novel coronavirus (SARS-CoV-2), antiviral drug discovery is of great importance. AutoDock Vina was used to screen potential drugs by molecular docking with the structural protein and non-structural protein sites of new coronavirus. Ribavirin, a common antiviral drug, remdesivir, chloroquine and luteolin were studied. Honeysuckle is generally believed to have antiviral effects in traditional Chinese medicine. In this study, luteolin (the main flavonoid in honeysuckle) was found to bind with a high affinity to the same sites of the main protease of SARS-CoV-2 as the control molecule. Chloroquine has been proved clinically effective and can bind to the main protease; this may be the antiviral mechanism of this drug. The study was restricted to molecular docking without validation by molecular dynamics simulations. Interactions with the main protease may play a key role in fighting against viruses. Luteolin is a potential antiviral molecule worthy of attention.