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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The threat, which originated in Wuhan, China, swiftly became an international emergency. Using a combination of a structure-based virtual screening and biochemical assay, this study seeks possible therapeutic candidates that specifically target the viral spike protein. Using virtual screening and inhibitory experiments, we identified acetyl keto-boswellic acid AKBA as a promising molecule for spike protein, which encouraged us to scan the rest of AKBA derivatives in our in-house database via 2D-similarity searching. Those hits declared significant interactions at the RBD interface, best possess and excellent drug-likeness and pharmacokinetics properties with high gastrointestinal absorption GIA without toxicity and allergenicity. The compounds C3 These findings demonstrate that these molecules particularly inhibit the function of spike protein and, therefore have the potential to be evaluated as drug candidates against SARS-CoV A novel coronavirus infection epidemic COVID was identified in December in Wuhan city, Hubei province, when the first case manifested with pneumonia-like symptoms in seafood and live animal markets in China 1. The symptoms of this disease in patients included fever, difficulty in breathing, malaise, dry cough, and dyspnea 2. Talking, coughing, and sneezing contribute to the spread of COVID because infected people expel infectious virus particles into the air 3 , 4. Responsible for the Middle East respiratory syndrome outbreak in 5. The transmembrane spike S glycoprotein, projecting from the viral surface, mediates coronavirus entrance into host cells. Spike S comprises two functional subunits, S1 and S2, that collaborate to connect to the angiotensin-converting enzyme 2 ACE2 receptor on the host cell and fuse the viral and cellular membranes S2 subunit 6. TM protease serine 2 TMPRSS2 , a type 2 TM serine protease localized on the host cell membrane, activates the Spike protein upon binding to the receptor, hence facilitating viral entrance into the cell 8. As the virus enters the human lung cell, they release its RNA and use the host machinery to make its copies 9. Attachment of the SARS-CoV-2 virus to host cell receptors requires the RBD S1 subunit of spike protein, therefore by specifically inhibiting this subunit, virus's access to the host cell can be restricted, and consequently viral genome's replication within the host cell can be impeded To combat this highly contagious infectious agent, researchers may search for new compounds that can precisely block the RBD and h ACE2 interaction using bioinformatics tools, in silico methods, and inhibition assay 14 , Up to date there is, no specific medications that have been approved to treat the distinct coronavirus infection. However, clinical trials of synthetic drug compounds have been started to evaluate coronavirus treatments Mostly synthetics drugs in clinical trials are inhibiting the viral protein Overcoming the issue of SARS-CoV-2 genome change and viral resistance to medicines and vaccines over time remains a challenge 18 , 19 , 20 , To get beyond this obstacle small, naturally occurring substances with inhibitory properties could prevent the SARS CoV-2 spike protein from interacting with the hACE2 receptor 22 , When compared to synthesized medications, naturally occurring or derived substances typically have less side effects and are more effective in blocking enzymes and proteins Natural substances have been refined by the elements to engage specifically with biological targets while having a low immunological response and good absorption The AKBA is a naturally derived compound from Boswellia serrata and have uses against antiviral and chronic inflammatory diseases of the lung 26 , So based on potent inhibition activity of AKBA in this study we aim to discover potential inhibitors from its derivatives against spike protein receptor binding domain. The docking site for compounds was selected from the protein—protein interface where the human ACE2 receptor binds with the Spike protein RBD domain. Afterward, the docked library was ranked based on the top docking score i. The schematic workflow of this study is presented in Fig. Comparison of fingerprints is the most common approach to discover the structural similarities between compounds. By using ProTox-II server 46 , various toxicity parameters of compounds, such as rat oral median lethal dose LD50 , hepatotoxicity, carcinogenicity, mutagenicity, immunotoxicity, and cytotoxicity were predicted. The allergenicity of selected compounds was predicted using the server CHAIPred 47 because some of the small inhibitors after binding to a specific protein can elicit immune response The selected natural compounds obtained through virtual screening and by 2D similarity searches were tested by inhibitory assay of the spike protein. The following calculation was used to calculate the percent inhibition using the SoftMax Pro and Excel software programs. The compounds which show high inhibition rate were further subjected to MD simulation to confirm their binding stability with protein. To simplify the simulation of protein—ligand interactions, the ff19SB force field parameterized the residues of the protein. When it comes to creating an optimal environment for protein—ligand interactions, water molecules play a vital role. Because of their importance to the simulations' hydration and stability, an octahedral OPC-water model was used to solvate the systems. Prior to the MD production run, the minimum energy state was achieved by a two-step energy reduction method. By reorganizing the atoms in the system, we can reduce the amount of stress and steric conflicts that exist The steepest descent algorithm, a gradient-based optimization method, was initially applied for 50, steps It iteratively adjusts the positions of the atoms in the system by following the negative gradient of the potential energy until a local minimum is reached. After the initial steepest descent minimization, another 25, iterations with the conjugate gradient approach were performed Another optimization method that quickly reaches a local minimum by merging data from earlier iterations is the conjugate gradient method. During the process of minimizing the energy, the water molecules were free to move while the protein residues were held in place. This calms the protein—ligand complex by allowing water molecules to equalize around the protein. Before the dynamic production runs, the systems must be gradually equilibrated at the desired temperature and pressure. Using a Langevin thermostat, the systems were gradually heated from a lower temperature to the target simulation temperature K at ps The Langevin thermostat maintains the system heated by subjecting them to random forces that are supposed to represent their interaction with a heat bath. During heating, the kinetic energy was adjusted for dynamic propagation using the Langevin thermostat with a collision frequency value of 2. This makes for an easily achieved target temperature in the system. Any potential steric conflicts were weeded out by the SHAKE algorithm before the dynamic production run SHAKE is a constraint algorithm that keeps hydrogen-atom covalent bonds stable, letting the simulation run for a longer period. After heating, density adjustment was performed in a ps run with the same protocol. This permits water molecules to settle around the protein—ligand complex and completes the equilibration of the system at the desired temperature. Subsequently, each system was equilibrated for ps at K under the NPT ensemble, which means the number of particles N , Pressure P , and Temperature T were kept constant. During this equilibration, no restrictions were placed on the arrangement of the atoms, so the system was free to investigate all possible phases. The production MD run, the meat of the simulations in which data for analysis and insights into protein—ligand interactions are obtained, could begin once the systems had equilibrated. Each system underwent a production run of ns Beyond this point, interactions are ignored, which allows the simulation to run faster without compromising accuracy. These trajectories capture the atomic positions and velocities of the protein and inhibitors ligand pair, which can be examined to determine the changes in the system. By averaging the positions of the atoms in the input frames denoted by x, we were able to get the RMSF of the atom i of interest. Using the Rg Radius of gyration, we were able to calculate the locations and velocities of the atoms at each time step First, Eq. Principal Components were obtained by firstly computing the covariance matrix C. The eigenvalue and eigenvector of the matrix were then calculated after the matrix was diagonalized. The resultant principal components PCs characterize the motion descriptively, whereas the eigenvalues quantify that description The proportional impact of each eigenvector was included. To examine their changes, the first two PCs were displayed on a graph. Equation 5 was used to get the free energy of the Spike protein complex and its free APO form. MOE Origin-Pro was used to extract the ensemble of lowest energy structures for each system, and those structures were then utilized to generate all graphs. The detailed interaction of spike protein and h ACE2 receptor is given in Fig. There are different structural substructures or patterns in MACCS made up of atoms other than hydrogen. The inhibitor AKBA with good inhibition against spike protein was selected as a query. The binding modes of 19 AKBA derivatives were analyzed which showed that these molecules exhibit good scores and mediate good docking interaction. The docking predicted interaction of these compounds at molecular level, reflecting firm binding of compounds at RBD interface Table S1 and Fig. Therefore, the pharmacokinetic and drug-like characteristics were estimated for the selected inhibitors ligand against spike protein RBD. The selected compounds have molecular weights MW ranging from The predicted polarity and topological surface area TPSA are in an acceptable range from All the compounds obey Lipinski's rule of five. Indeed, molecules with molecular weights above Da may still be deemed drug-like provided they possess additional desirable characteristics, making the molecular weight criterion a flexible one 64 , Natural compounds such as those derived from plants, marine life, and microorganisms can have greater molecular weights than synthetic ones and can be employed as drugs or therapeutic agents. Antibiotics, anti-cancer drugs, and immunosuppressants drugs are a few examples 66 , 67 , Another crucial factor in determining oral bioavailability is molar refractivity MR , defined by the Ghose rule 69 , and its value, as per the Lipinski rule 62 , should range from 40 to for fulfilling the drug-likeness criteria by all compounds except A2, A6 , and C-6H. Besides, Ghose, Veber 70 , Egan 71 , and Muegge 72 rules were used to examine the drug-likeness of compounds. None of the compounds can cross the blood—brain barrier BBBP. Except for A3 , and A7 the other compounds do not display features typical of P-glycoprotein substrates. Besides these, all the compounds are non-allergic as predicted by CHAIPred and cannot elicit any kinds of immune response. The toxicity analysis as predicted by server ProTox-II for the selected compounds indicates that these compounds are non-toxic except the A4, A5, A6, C6F , and C6G which show immunotoxicity and only A5 shows cytotoxicity. The basic skeleton of these compounds is similar while the R group is varied. For instance, the invitro activity demonstrates that compound A1 with methanol substitution is inactive, in contrast, A2 and A3 with methyl 4-methyl benzenesulfonate and, azido methane substitutions, respectively exhibited good inhibitory capability with While inhibitory potency of A7 was somehow declined Similarly, compound C-3 with propyne substituent resulted in high inhibitory potential with The inhibitory potency of C6C and C6D was enhanced with the substitution of 1- 2-methoxyphenyl methyl-1H-1,2,3-triazole and 4-methyl 2- trifluoromethyl phenyl -1H-1,2,3-triazole, resulted in Interestingly, the substitution of 1- 4-methoxyphenyl methyl-1H-1,2,3-triazole in C3 and C 6E further increased its potency against RBD and was found to be the most active molecule with However, the inhibitory effect of C6J declined with the substitution of 1- 4-fluorophenyl methyl-1H-1,2,3-triazole While C6k with 4-methyl 4- trifluoromethyl phenyl -1H-1,2,3-triazole substitution exhibited To investigate the structural modifications that occur in proteins because of the binding of inhibitors compounds we used AMBER22 to simulate the interaction that would occur between Spike protein RBD and the compounds that were chosen. Based on good inhibition against spike protein RBD we select two compounds C3 and C6E for simulation to further confirm the docking interaction. The root-mean-square deviation RMSD was computed to gain an understanding of the degree to which the compounds diverged from their primary structure. A fluctuation of 2. The protein was stable through the entire simulation while a small rise was observed from 85 to 95 ns of 2. A small fluctuation of 1. The root mean square fluctuation RMSF is a measurement performed to assess the extent of deviation of an atomic position relative to its average position within the framework of a protein structure. In this study, the RMSF analysis was performed on the Spike protein—protein complex with specific compounds C3 and C6E to investigate the fluctuations of these compounds concerning the protein. Increased RMSF values after compound attachment suggested a more flexible structure, which indicated well for subsequent interactions with ligand molecules. The protein was stable at the end of the simulation while some fluctuation was observed at 38 ns 3. The residue fluctuation was observed at the start of the simulation at 35 ns 1. The compound was stable throughout the simulation while small residual fluctuation was detected at 38 ns of 2. For the ligand C6E, a small residual increase was observed at 38 ns 2. It is important in figuring out the radius of gyration because it gives a basic overview of an object's shape and helps forecast its behaviors under different conditions, considering things like stability, potential for energy transfer and preservation, and responsiveness to outside influences. The average Rog value for the APO form of protein is A small increase was observed from the start of the simulation till 98 ns Similarly, the average Rog value for spike protein 6MOJ was calculated For the inhibitor compound C3 the total Rog value was calculated as The compound was stable while showing an increase of 43 ns Similarly, the ligand C6E shows an average Rog value of At the start of the simulation, an increase in Rog value was observed from 25 to 65 ns The total mobility observed in the protein was calculated by the eigenvalues, for which the eigenvectors were calculated from the covariance matrix. Ten eigenvectors for each system were calculated to explore the dominant motions that contribute to the significant structural changes during simulation Fig. The motions observed in the protein were in the protein—protein interaction interface, where the loop B side shows significant structural modification Fig. The internal sheets of the structure went through structural confirmation upon binding with the h ACE2 protein. Meanwhile, the C6E system shows slight confirmation of the A loop position, and the B loop region shows most of the motions in the cartoon representation. Comparing the motions in the active state 6M0J and inhibited system C6E , they were opposite in direction, whereas the internal sheets in the C6E system do not show any structural modification stays blue. The C3 system cartoon representation from the ns simulation shows that the active site region of the protein depicts most of the structural confirmation of the C3 protein. The PCA results from the ns simulation of the spike protein's dynamics in free activated and inhibited states highlight key insights into structural mobility and interactions. The most significant movements were observed in the reference-activated system 6M0J and the C6E system, particularly at the protein—protein interaction interfaces and loop regions. These results represent valuable perspectives of the selected compounds for therapeutic design to emphasize the importance of targeting areas of high mobility and conformational changes within the spike protein to disrupt its function effectively. The cumulative movements derived from the top ten eigenvectors for each of these systems are expressed as percentages in the 2D graph. The color-coded cartoon representation transitions from blue to red and shows the regions of the protein from their initial state to their altered state at the ns simulation period. The residues region where the dominant motions were observed were highlighted in yellow. The spike RBD domain underwent structural conformation changes in the free state, activated and inhibited during the simulation run. To observe these changes, the PC1 and PC2 values were plotted against each other. The transitions of the protein during the simulation run and where it stays the most, at which confirmation was shown in the Fig. Three distinct confirmation clusters were observed in the APO system. The activated reference system 6M0J shows rapid conformational changes in the clusters. The behavior of the inhibitor-attached systems changed due to the inhibitor attachment with the protein active site. In the APO system, a progression through three conformation clusters was observed, with a significant duration in the final cluster, while the activated 6M0J system showed quicker conformational transitions, ultimately stabilizing in its final cluster. Color coding was utilized to represent the density of frames over the simulation from blue, green, and yellow, where yellow means high density. The clusters within each system were labeled A, B, and C, and the simulation duration for which the system remained in each cluster was represented as a percentage. To further explore the direction and magnitude of the principal movements, porcupine plots were constructed for each system Fig. In the porcupine plot, the arrow length shows the magnitude of the motion caused in the residue positions, while the arrowhead shows the direction of the movement. The free state spike protein APO shows a close confirmation in the porcupine plot, where the active site residues move toward the active site region. In contrast, the magnitude and direction of the movements change in the active state of the 6M0J system. Comparing the APO and activated state 6M0J with the C3 inhibited state, the behavior of movement in the inhibited system was changed. The active pocket of the C3 inhibitor attached system moves outward, which retains an open conformation of the spike RBD. Similarly, the C6E follows the pattern of the C3 system, where the active pocket moves away from the center of the active site. The C3 system shows a higher magnitude of movement when compared with the C6E system. The outcomes from the porcupine plot results show distinct movement patterns of spike RBD protein in free, active, and inhibited states. In the free state spike RBD APO , active site residues converged towards the center of the active site, which indicates a compact conformation, while the active state 6M0J displayed divergent movement, having one side of the active pocket shifting towards the active site and affecting the helices in the active pocket vicinity. The arrow size indicates the extent of movement, and the arrow's orientation reveals the direction of the motion. Hydrogen bonds are essential in maintaining the structure and function of biological molecules. In molecular dynamic simulations, they play a crucial role in determining the dynamics and stability of molecular systems. The bond lifetime between the ligands and these residues ranged from The investigation of hydrogen bond interactions revealed that the chosen chemicals establish strong bonds with the key residues present in the active pocket of Spike protein Table S5. Because it can provide information about the strength of a protein—ligand interaction, the use of estimated binding free energy is important in the field of drug design. This in turn makes it easier to assess potential chemicals' binding affinities. Several investigations towards blocking SARS CoV-2 entry into the host cell have focused on the spike protein 79 , 80 , 81 , 82 , Also, vaccines have been developed as an effective agents but still possess some modest side effects 84 , 85 , Over time, viruses can undergo mutations that lead to the formation of new versions that can either fully or partially prevent immunization and develop resilience to current medications and vaccines. The creation of novel inhibitors may offer substitute therapeutic approaches that are successful in combating newly developing variations. Designing inhibitors against the spike protein could aim for a broad-spectrum effect, targeting multiple variants or even different coronaviruses. Since drugs developed to treat SARS-CoV-2 could provide an effective first line of defense against future coronaviruses, their development is more rational and preferable Similarly, in-silico methods are becoming increasingly significant in the pharmaceutical industry In-silico medication design affects the overall drug development schedule by facilitating the quick identification and discovery of innovative therapeutic medicines 88 , 89 , 90 , Herein, we employed a combination of computational methods like structure-based virtual screening and 2D-similarity searching and an enzyme inhibition bioassay to uncover novel potential inhibitors of SARS-CoV-2 spike protein. In this study, the crystal structure of the spike protein receptor binding domain RBD was taken together with the human h ACE2 receptor. The natural products and their derived compounds were targeted against spike protein through virtual screening. The docking analysis helps strengthen the protein—ligand bond, suggesting a strong binding affinity between ligands and spike protein RBD. The pharmacokinetics of these compounds showed their appropriate drug-like properties with no toxicity and allergenicity. Based on good docking score, binding position, and pharmacokinetics properties, these compounds were further subjected to in vitro inhibition assay to confirm their drug candidacy. Due to high inhibition potential against spike protein RBD the top compounds C3 and C6E docking interaction were confirmed by molecular dynamic simulation. Based on the medicinal implications of AKBA, and good inhibitory sresults in our current findings, these newly identified spike protein inhibitors appeal further investigation to be used as possible drug candidates to tackle this severe infection Supplementary Information. After discovering that acetyl keto-boswellic acid AKBA is a potential compound for spike protein through virtual screening and inhibitory tests, we scanned the remaining AKBA derivatives in our in-house database using 2D-similarity searching. Our in-silico results were subsequently corroborated by in vitro bioassay. The docking interaction of highly inhibitory potential potent compounds have further confirm by MD simulation which give us a good binding energy. Yuki, K. Hafeez, A. Ejmo 4 , — Google Scholar. Scottish Med. Article Google Scholar. Bowleg, L. Public Health Assoc. Babaahmadi, V. Biodegradable and multifunctional surgical face masks: A brief review on demands during COVID pandemic, recent developments, and future perspectives. Total Env. Ibrahim, I. Banerjee, A. Preprints , Smith, M. Liu, Z. Tian, F. BioRxiv , Koley, T. Structural analysis of COVID spike protein in recognizing the ACE2 receptor of different mammalian species and its susceptibility to viral infection. 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In silico pharmacology: Computer-aided methods could transform drug development. Ali, S. Vakilian, S. Qurishi, Y. Potential role of natural molecules in health and disease: Importance of boswellic acid. Plants Res. Sethi, V. Fatima, S. Plus 2 , Trivedi, V. Anticancer properties of boswellic acids: Mechanism of action as anti-cancerous agent. Caliebe, R. Download references. You can also search for this author in PubMed Google Scholar. All authors have read and approved the final version of the manuscript. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Reprints and permissions. Identification of new pharmacophore against SARS-CoV-2 spike protein by multi-fold computational and biochemical techniques. Sci Rep 14 , Download citation. Received : 06 August Accepted : 06 February Published : 13 February Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Download PDF. Subjects Chemical biology Computational biology and bioinformatics. Introduction A novel coronavirus infection epidemic COVID was identified in December in Wuhan city, Hubei province, when the first case manifested with pneumonia-like symptoms in seafood and live animal markets in China 1. Figure 1. Some already reported compounds for anti-viral activities. Full size image. Figure 2. Schematic workflow of design study. Figure 3. Table 1 Chemical structures of the selected hits for in-vitro testing. Full size table. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. Figure 9. Figure Table 3 Binding free energy of the simulated inhibitor compounds C3 and C6E. Data availability All data generated or analyzed during this study are included in this published article. References Yuki, K. Article Google Scholar Bowleg, L. Article Google Scholar Babaahmadi, V. Google Scholar Smith, M. Google Scholar Liu, Z. Google Scholar Koley, T. Article Google Scholar Hussain, M. Google Scholar Rosa, S. Article Google Scholar Chang, C. Article Google Scholar Khan, A. Article Google Scholar Pearse, W. Google Scholar Hussain, N. Google Scholar Papageorgiou, L. Google Scholar Waqas, M. Google Scholar Banerjee, P. Article Google Scholar Bergonzo, C. Google Scholar Avdeef, A. Article Google Scholar Bhattacharyya, J. Article Google Scholar Veber, D. Article Google Scholar Mir, J. Google Scholar Ho, T. Article Google Scholar Jeyanathan, M. Article Google Scholar Sprent, J. Google Scholar Terstappen, G. Google Scholar Fatima, S. View author publications. Ethics declarations Competing interests The authors declare no competing interests. Additional information Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information. About this article. Cite this article Ullah, A. Copy to clipboard. Sharanya D. Publish with us For authors Language editing services Submit manuscript. Search Search articles by subject, keyword or author. 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