D. S. Bodun, D. Omoboyowa, T. Balogun, Abigail Osinachi Enyinnaya
The rising prevalence of diabetes necessitates continued research into natural antidiabetic medicines that target a key biochemical enzyme involved. The α-amylase enzyme is involved in the digestion of starch, glycogen, and disaccharides in the gastrointestinal tract. Its essential roles and distinct properties make it an effective antidiabetic target. This work aimed to use in silico approaches to find possible α-amylase inhibitors from Combretum micranthum bioactive substances. On the Schrödinger Maestro 12.5, over 50 C. micranthum compounds were screened, followed by MM-GBSA and ADMET (absorption, distribution, metabolism, excretion, and toxicity) studies of the highest affinity compounds. The α-amylase binding affinities were higher for rutin trihydrate and myricetin-3-rutinoside (-12.162 kcal/mol and -10.935 kcal/mol, respectively). They reacted with amino acids that are required for the inhibition of α-amylase. As a result, these compounds have the structural characteristics, binding affinities, and molecular interactions necessary as α-amylase inhibitors and could be turned into antidiabetic medicines through lead optimization and experimental research.
{"title":"Identification of Bioactive Molecules from Combretum micranthum as Potential Inhibitors of α-amylase through Computational Investigations","authors":"D. S. Bodun, D. Omoboyowa, T. Balogun, Abigail Osinachi Enyinnaya","doi":"10.33084/jmd.v2i2.3673","DOIUrl":"https://doi.org/10.33084/jmd.v2i2.3673","url":null,"abstract":"The rising prevalence of diabetes necessitates continued research into natural antidiabetic medicines that target a key biochemical enzyme involved. The α-amylase enzyme is involved in the digestion of starch, glycogen, and disaccharides in the gastrointestinal tract. Its essential roles and distinct properties make it an effective antidiabetic target. This work aimed to use in silico approaches to find possible α-amylase inhibitors from Combretum micranthum bioactive substances. On the Schrödinger Maestro 12.5, over 50 C. micranthum compounds were screened, followed by MM-GBSA and ADMET (absorption, distribution, metabolism, excretion, and toxicity) studies of the highest affinity compounds. The α-amylase binding affinities were higher for rutin trihydrate and myricetin-3-rutinoside (-12.162 kcal/mol and -10.935 kcal/mol, respectively). They reacted with amino acids that are required for the inhibition of α-amylase. As a result, these compounds have the structural characteristics, binding affinities, and molecular interactions necessary as α-amylase inhibitors and could be turned into antidiabetic medicines through lead optimization and experimental research.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74215950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Coronavirus Infectious Disease-19 (COVID-19) caused by coronavirus 2 is a global health hazard. The lack of medications against the disease is a major concern of the research community today. Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease (SARS-CoV-2 MPro) is the most extensively studied protein responsible for spreading disease. Several plant-based products are utilized to treat the disease's symptoms. Here, we have attempted to screen 377 phytocompounds against the target computationally. We have sorted eight best-pose compounds based on docking studies for further analysis. Lipinski and Adsorption, Distribution, Metabolism, Elimination/Toxicity (ADME/T) properties were also evaluated to assess the drug-like properties and toxicity of the screened compounds. Finally, we discovered Coruscanone to be the most effective lead compound for the target. The best complex was further undertaken for dynamic simulation. RMSD, RMSF, h-bond, and Rg were analyzed and studied related to the reference compound. The study additionally continues to elucidate its inhibitory action via in vitro studies.
{"title":"Docking and Dynamics Study of Phytochemicals as Potent Inhibitors against SARS-CoV-2 Main Protease","authors":"Palla Ramprasad, A. Babu, Suveena Sukumaran","doi":"10.33084/jmd.v2i2.3969","DOIUrl":"https://doi.org/10.33084/jmd.v2i2.3969","url":null,"abstract":"Coronavirus Infectious Disease-19 (COVID-19) caused by coronavirus 2 is a global health hazard. The lack of medications against the disease is a major concern of the research community today. Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease (SARS-CoV-2 MPro) is the most extensively studied protein responsible for spreading disease. Several plant-based products are utilized to treat the disease's symptoms. Here, we have attempted to screen 377 phytocompounds against the target computationally. We have sorted eight best-pose compounds based on docking studies for further analysis. Lipinski and Adsorption, Distribution, Metabolism, Elimination/Toxicity (ADME/T) properties were also evaluated to assess the drug-like properties and toxicity of the screened compounds. Finally, we discovered Coruscanone to be the most effective lead compound for the target. The best complex was further undertaken for dynamic simulation. RMSD, RMSF, h-bond, and Rg were analyzed and studied related to the reference compound. The study additionally continues to elucidate its inhibitory action via in vitro studies.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74100708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Resistance against anti-tubercular drugs is a significant problem. This elucidates the need for novel drug targets. Altering and targeting the enzymes involved in cell wall synthesis led to fatal damage to the bacterial cell. Mycolic acids are critically responsible for the virulence of Mycobacterium Tuberculosis. This pathway represents an essential reservoir of novel targets for developing new TB drugs. The study aims to identify phytochemicals with the capacity to bind with enzymes of mycolic acid synthesis pathways. This study shows the interaction between phytochemicals and proteins responsible for mycolic acid synthesis is shown through bioinformatics & molecular docking tools. Docking showed binding affinity between protein molecules of the mycolic acid synthesis pathway and ligand molecules in the study. PKS13 (polyketide synthase) interacts with the ligand beta-amyrin acetate with a vina score of -7.1 Kcal/mol. At the same time, its binding energy with Piperine is -6.8 Kcal/mol. DprE1 (Decaprenylphosphoryl-bet-D-ribose-2-epimerase), the other protein docked with beta-amyrin acetate, showed a vina score of -9.7 Kcal/mol binding energy. Piperine with DprE1 exhibits interaction with a score of -8.3 Kcal/mol. Beta-amyrin acetate is docked with a score of -6.9 Kcal/mol against KasA (Beta-ketoacyl-acyl carrier protein synthase). On the other hand, Piperine with KasA gave a result of -7.0 Kcal/mol. Piperine and Beta-amyrin acetate binds to PKS13, DprE1 & KasA protein/enzymes responsible for mycolic acid biosynthesis.
{"title":"Phytochemical Molecules Binding with the Proteins of Mycolic Acid Synthesis Pathway of Mycobacterium tuberculosis","authors":"Rishabh Gaur, Praveen Anand","doi":"10.33084/jmd.v2i2.4074","DOIUrl":"https://doi.org/10.33084/jmd.v2i2.4074","url":null,"abstract":"Resistance against anti-tubercular drugs is a significant problem. This elucidates the need for novel drug targets. Altering and targeting the enzymes involved in cell wall synthesis led to fatal damage to the bacterial cell. Mycolic acids are critically responsible for the virulence of Mycobacterium Tuberculosis. This pathway represents an essential reservoir of novel targets for developing new TB drugs. The study aims to identify phytochemicals with the capacity to bind with enzymes of mycolic acid synthesis pathways. This study shows the interaction between phytochemicals and proteins responsible for mycolic acid synthesis is shown through bioinformatics & molecular docking tools. Docking showed binding affinity between protein molecules of the mycolic acid synthesis pathway and ligand molecules in the study. PKS13 (polyketide synthase) interacts with the ligand beta-amyrin acetate with a vina score of -7.1 Kcal/mol. At the same time, its binding energy with Piperine is -6.8 Kcal/mol. DprE1 (Decaprenylphosphoryl-bet-D-ribose-2-epimerase), the other protein docked with beta-amyrin acetate, showed a vina score of -9.7 Kcal/mol binding energy. Piperine with DprE1 exhibits interaction with a score of -8.3 Kcal/mol. Beta-amyrin acetate is docked with a score of -6.9 Kcal/mol against KasA (Beta-ketoacyl-acyl carrier protein synthase). On the other hand, Piperine with KasA gave a result of -7.0 Kcal/mol. Piperine and Beta-amyrin acetate binds to PKS13, DprE1 & KasA protein/enzymes responsible for mycolic acid biosynthesis.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85565477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tope Abraham Ibisanmi, Jamiu Olaseni Aribisala, Peace Ifeoma Odjegba, Damilola Ademuyi, Ayomide Akinmusere, Faith I Ajayi
The difficulty in treating cancer resides in targeting abnormal proliferation while protecting normal proliferation, necessitating a thorough comprehension of the normal and malignant mechanisms that promote cell growth and proliferation. Targeting cell death signaling pathways such as glycolytic and mitochondrial apoptosis is the hallmark of many cancers, the aim of which this research is ready to evaluate. Atomistic molecular dynamics simulation of top hits after molecular docking and ADMET profiling of the ligands were performed for main protease-hit complexes. Docking scores of ligands used against PKM2 range from –9.36 to –12.1 kcal/mol, wherein momordicoside-F2 had the highest score (2.1 kcal/mol), performing better than the FDA-approved drug benserazide. Likewise, the scores ranged between –8.51 and –12.05 kcal/mol for Anti-apoptotic Myeloid Leukemia 1 (MCL-1), with momordicoside-F1 being the highest-ranked compound. The RMSD plots depicted stable trajectories with consistent and minor fluctuations implying that the protein (PKM2 and MCL1) backbone underwent minor structural perturbations. In addition, several significant peaks of increased fluctuations were also observed, indicating their increased interaction potential, implying that the ligands could adapt well in the protein's binding pocket. The SASA analysis results show that the ligands retained inside their shallow binding pocket. The phylogenetic tree obtained implies the likelihood of recurring results of the in silico profiling. Conclusively, this research unveils that Mormordicoside F1 shows good stability with MCL-1, likewise, momordicoside-F2 against PKM2. These hits can be a better re-purposing option.
{"title":"De Novo Class of Momordicoside with Potent and Selective Tumor Cell Growth Inhibitory Activity as Pyruvate Kinase Muscle Isozyme 2 and Anti-apoptotic Myeloid Leukemia 1 Inhibitors","authors":"Tope Abraham Ibisanmi, Jamiu Olaseni Aribisala, Peace Ifeoma Odjegba, Damilola Ademuyi, Ayomide Akinmusere, Faith I Ajayi","doi":"10.33084/jmd.v2i2.4006","DOIUrl":"https://doi.org/10.33084/jmd.v2i2.4006","url":null,"abstract":"The difficulty in treating cancer resides in targeting abnormal proliferation while protecting normal proliferation, necessitating a thorough comprehension of the normal and malignant mechanisms that promote cell growth and proliferation. Targeting cell death signaling pathways such as glycolytic and mitochondrial apoptosis is the hallmark of many cancers, the aim of which this research is ready to evaluate. Atomistic molecular dynamics simulation of top hits after molecular docking and ADMET profiling of the ligands were performed for main protease-hit complexes. Docking scores of ligands used against PKM2 range from –9.36 to –12.1 kcal/mol, wherein momordicoside-F2 had the highest score (2.1 kcal/mol), performing better than the FDA-approved drug benserazide. Likewise, the scores ranged between –8.51 and –12.05 kcal/mol for Anti-apoptotic Myeloid Leukemia 1 (MCL-1), with momordicoside-F1 being the highest-ranked compound. The RMSD plots depicted stable trajectories with consistent and minor fluctuations implying that the protein (PKM2 and MCL1) backbone underwent minor structural perturbations. In addition, several significant peaks of increased fluctuations were also observed, indicating their increased interaction potential, implying that the ligands could adapt well in the protein's binding pocket. The SASA analysis results show that the ligands retained inside their shallow binding pocket. The phylogenetic tree obtained implies the likelihood of recurring results of the in silico profiling. Conclusively, this research unveils that Mormordicoside F1 shows good stability with MCL-1, likewise, momordicoside-F2 against PKM2. These hits can be a better re-purposing option.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"316 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80112194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Erum Zafar, Zainab Ahsan, M. Maqbool, Aqsa Zaman, Sameena Gul, Amara Maryam, Muhammad Khan, H. A. Shakir, M. Irfan
The novel strain of coronavirus, SARS-CoV-2, has spread adverse effects on human health with high mortality rates worldwide. SARS-CoV-2 is a severe respiratory disease expressed through positive single stranded RNA enveloped virus. SARS-CoV-2 had affected globally and is influencing the economy as well. The rapidly spreading coronavirus infection has discombobulated the researchers in perpetuate search for different or effective therapeutic drugs. Most of the connatural products are proposed to have significant clinical outcomes but their pathways of action are not clear. This molecular docking study presents alantolactone, a bio-active member of sesquiterpene family as a successful inhibitor of SARS-Cov-2 and human receptor proteins. Alantolactone shows high binding affinity with the SARS-CoV-2 target proteins such as spike glycoprotein (S-protein), nucleocapsid protein (N-protein), main protease (MPro), and papain-like protease (PLPro) with a binding affinity of -7.3 kcal/mol, -7.9 kcal/mol, -6.8 kcal/mol, and -7.1 kcal/mol, respectively as well as human receptor proteins associated with the recognition, binding and biogenesis of SARS-CoV-2 such as angiotensin-converting enzyme 2 (ACE-2), receptor binding domain (S1-RBD) and ACE2 interphase, furin, adaptor-associated protein kinase 1 (AAK1), cyclin G-associated kinase (GAK), and both closed and open configurations of the two-pore channel (TPC2) with binding energies of -6.7 kcal/mol, - 6.9 kcal/mol, -8.1 kcal/mol, -7.3 kcal/mol, and -7.9 kcal/mol, respectively. Molecular docking and ADMET properties and toxicity predictions suggest that alantolactone could effectively binds with various viral target protein and human target proteins and could be developed into a novel SARS-coV-2 inhibitor.
{"title":"Alantolactone: A Potential Multitarget Drug candidate for Prevention of SARS-CoV-2 Cell Entry","authors":"Erum Zafar, Zainab Ahsan, M. Maqbool, Aqsa Zaman, Sameena Gul, Amara Maryam, Muhammad Khan, H. A. Shakir, M. Irfan","doi":"10.33084/jmd.v2i2.3679","DOIUrl":"https://doi.org/10.33084/jmd.v2i2.3679","url":null,"abstract":"The novel strain of coronavirus, SARS-CoV-2, has spread adverse effects on human health with high mortality rates worldwide. SARS-CoV-2 is a severe respiratory disease expressed through positive single stranded RNA enveloped virus. SARS-CoV-2 had affected globally and is influencing the economy as well. The rapidly spreading coronavirus infection has discombobulated the researchers in perpetuate search for different or effective therapeutic drugs. Most of the connatural products are proposed to have significant clinical outcomes but their pathways of action are not clear. This molecular docking study presents alantolactone, a bio-active member of sesquiterpene family as a successful inhibitor of SARS-Cov-2 and human receptor proteins. Alantolactone shows high binding affinity with the SARS-CoV-2 target proteins such as spike glycoprotein (S-protein), nucleocapsid protein (N-protein), main protease (MPro), and papain-like protease (PLPro) with a binding affinity of -7.3 kcal/mol, -7.9 kcal/mol, -6.8 kcal/mol, and -7.1 kcal/mol, respectively as well as human receptor proteins associated with the recognition, binding and biogenesis of SARS-CoV-2 such as angiotensin-converting enzyme 2 (ACE-2), receptor binding domain (S1-RBD) and ACE2 interphase, furin, adaptor-associated protein kinase 1 (AAK1), cyclin G-associated kinase (GAK), and both closed and open configurations of the two-pore channel (TPC2) with binding energies of -6.7 kcal/mol, - 6.9 kcal/mol, -8.1 kcal/mol, -7.3 kcal/mol, and -7.9 kcal/mol, respectively. Molecular docking and ADMET properties and toxicity predictions suggest that alantolactone could effectively binds with various viral target protein and human target proteins and could be developed into a novel SARS-coV-2 inhibitor.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85884562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F. A. Ugbe, G. Shallangwa, A. Uzairu, I. Abdulkadir
Lymphatic filariasis and onchocerciasis are two common filarial diseases caused by a group of parasitic nematodes called filarial worms, which co-habit with the bacteria organism Wolbachia. One good treatment approach seeks Wolbachia as a drug target. Here, a computer-aided molecular docking screening was conducted on a series of 52 pleuromutilin analogs against four Wolbachia enzymes: α-DsbA1 (PDB: 3F4R), α-DsbA2 (6EEZ), OTU deubiquitinase (6W9O), and cytoplasmic incompatibility factor CidA (7ESX) to find a more potent drug candidate(s) for the treatment of filarial diseases. The docking investigation was performed using the iGEMDOCK tool, while NAMD was utilized for the Molecular Dynamic (MD) simulation. The results of the virtual screening identified four ligand-protein interaction pairs with the highest binding affinities in the order: 17_6W9O (-117.31 kcal/mol) > 28_6EEZ (-104.43 kcal/mol) > 17_7ESX (-102.56 kcal/mol) > 41_7ESX (-101.51 kcal/mol), greater than that of the reference drug doxycycline_7ESX (-92.15 kcal/mol). These molecules (17, 28, and 41) showed excellent binding interactions, making very close contact with the receptors’ amino acid residues. They also showed better pharmacokinetic properties than doxycycline because they showed high intestinal absorption, were orally bioavailable and showed no AMES toxicity. Also, the stability of 17_6W9O interactions was confirmed by the MD simulation. Therefore, the selected molecules could be developed as potential drug candidates for treating filarial diseases.
{"title":"Molecular Docking Screening and Pharmacokinetic Studies of Some Boron-Pleuromutilin Analogues against Possible Targets of Wolbachia pipientis","authors":"F. A. Ugbe, G. Shallangwa, A. Uzairu, I. Abdulkadir","doi":"10.33084/jmd.v2i1.3450","DOIUrl":"https://doi.org/10.33084/jmd.v2i1.3450","url":null,"abstract":"Lymphatic filariasis and onchocerciasis are two common filarial diseases caused by a group of parasitic nematodes called filarial worms, which co-habit with the bacteria organism Wolbachia. One good treatment approach seeks Wolbachia as a drug target. Here, a computer-aided molecular docking screening was conducted on a series of 52 pleuromutilin analogs against four Wolbachia enzymes: α-DsbA1 (PDB: 3F4R), α-DsbA2 (6EEZ), OTU deubiquitinase (6W9O), and cytoplasmic incompatibility factor CidA (7ESX) to find a more potent drug candidate(s) for the treatment of filarial diseases. The docking investigation was performed using the iGEMDOCK tool, while NAMD was utilized for the Molecular Dynamic (MD) simulation. The results of the virtual screening identified four ligand-protein interaction pairs with the highest binding affinities in the order: 17_6W9O (-117.31 kcal/mol) > 28_6EEZ (-104.43 kcal/mol) > 17_7ESX (-102.56 kcal/mol) > 41_7ESX (-101.51 kcal/mol), greater than that of the reference drug doxycycline_7ESX (-92.15 kcal/mol). These molecules (17, 28, and 41) showed excellent binding interactions, making very close contact with the receptors’ amino acid residues. They also showed better pharmacokinetic properties than doxycycline because they showed high intestinal absorption, were orally bioavailable and showed no AMES toxicity. Also, the stability of 17_6W9O interactions was confirmed by the MD simulation. Therefore, the selected molecules could be developed as potential drug candidates for treating filarial diseases.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74922750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nahid Fatema, V. Manga, L. Yamini, S. Khan, Q. Ullah
The selective blockade of 5HT7R (5-hydroxytryptamine 7 receptor) displays an antidepressant-like activity. It is a Gs-coupled receptor, which inactivates the adenyl cyclase enzyme or activates the potassium ion channel. Structural information of 5HT7 was obtained by homology modeling using MODELLER v.9.13. In the present study, pharmacophore-based virtual screening, molecular docking, and binding free energy calculations were performed on a series of antagonist aryl sulphonamide derivatives. A five-point pharmacophore hypothesis with two hydrogen bond acceptor (A), one hydrogen bond donor (D), one positive group (p), and one ring (R) was developed with acceptable R2 and Q2 values of 0.90 and 0.602, respectively. Eventually, common pharmacophore hypothesis-based screening was conducted against Asinex databases. Finally, binding free energy and dock score analysis was carried out for the top hits obtained from the docking process. All 14 hits from the database in this study had a satisfactory dock score and binding energy values within the best active compound range. H bond interaction with amino acid residues Ser212 and π-π stacking with Tyr249 were investigated for the best active molecule. Both are present in the top hits, including other interactions as well.
{"title":"Pharmacophore Based Virtual Screening and Docking of Different Aryl Sulfonamide Derivatives of 5HT7R Antagonist","authors":"Nahid Fatema, V. Manga, L. Yamini, S. Khan, Q. Ullah","doi":"10.33084/jmd.v2i1.3165","DOIUrl":"https://doi.org/10.33084/jmd.v2i1.3165","url":null,"abstract":"The selective blockade of 5HT7R (5-hydroxytryptamine 7 receptor) displays an antidepressant-like activity. It is a Gs-coupled receptor, which inactivates the adenyl cyclase enzyme or activates the potassium ion channel. Structural information of 5HT7 was obtained by homology modeling using MODELLER v.9.13. In the present study, pharmacophore-based virtual screening, molecular docking, and binding free energy calculations were performed on a series of antagonist aryl sulphonamide derivatives. A five-point pharmacophore hypothesis with two hydrogen bond acceptor (A), one hydrogen bond donor (D), one positive group (p), and one ring (R) was developed with acceptable R2 and Q2 values of 0.90 and 0.602, respectively. Eventually, common pharmacophore hypothesis-based screening was conducted against Asinex databases. Finally, binding free energy and dock score analysis was carried out for the top hits obtained from the docking process. All 14 hits from the database in this study had a satisfactory dock score and binding energy values within the best active compound range. H bond interaction with amino acid residues Ser212 and π-π stacking with Tyr249 were investigated for the best active molecule. Both are present in the top hits, including other interactions as well.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89167099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
VlsE is the key enzyme in antibacterial and suicide antigenic variation. While the vlsE of Borrelia burgdorferi sensu lato complex causes Lyme disease. Therefore, vlsE is considered a significant drug target for Lyme disease. In this paper, we report the model of the three-dimensional structure of vlsE resulting from a homology modeling study. Homology modeling was developed using three different software and evaluating the best model. Subsequent docking studies of the natural substrate tetradecane and known antibacterial drugs were performed with SwissDock and shed new light on the binding characteristics of the enzyme. Binding energies ranged from -2024.12 to -2032.17 kcal/mol. As a result, they might be synthesized further and developed into active commercial antibacterial drugs.
{"title":"Homology Modeling and Molecular Docking Studies of Selected Substituted Tetradecane on vlsE Borrelia spielmanii","authors":"Venu Paritala, Harsha Thummala, Talluri Naga Santosh Mohith","doi":"10.33084/jmd.v2i1.3407","DOIUrl":"https://doi.org/10.33084/jmd.v2i1.3407","url":null,"abstract":"VlsE is the key enzyme in antibacterial and suicide antigenic variation. While the vlsE of Borrelia burgdorferi sensu lato complex causes Lyme disease. Therefore, vlsE is considered a significant drug target for Lyme disease. In this paper, we report the model of the three-dimensional structure of vlsE resulting from a homology modeling study. Homology modeling was developed using three different software and evaluating the best model. Subsequent docking studies of the natural substrate tetradecane and known antibacterial drugs were performed with SwissDock and shed new light on the binding characteristics of the enzyme. Binding energies ranged from -2024.12 to -2032.17 kcal/mol. As a result, they might be synthesized further and developed into active commercial antibacterial drugs.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81498610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David Mora-Martinez, Jorge Organista-Nava, J. Sandoval-Ramírez, B. Illades-Aguiar, A. Carrasco-Carballo
One of the main design features of enzyme regulators for the CYPs is the presence of a heme-group and different oxidation states in iron atoms. The selective inhibition of a CYP-enzyme can help to reduce the formation of steroidal molecules that causes undesirable disorders and is, therefore a topic of great biochemical-pharmaceutical interest. The present work carried out an analysis of effect on the coupling-energy of the iron core according to its changes from oxidation Fe(II) to Fe(III) state, over inhibitors and substrates, in a particular enzyme. Two crystals from CYP21A2, CYP11A1, CYP17A1 and CYP19A1 enzymes were selected, assigning the oxidation states separately in each case. It was highlighted that for CYP11A1 and CYP19A1 enzymes, no significant difference was observed in coupling energies between Fe oxidation state and crystal stereo-disposition. This last can be used to analyze their congruence towards the reported biological data. For CYP17A1, the ideal crystal for inhibitors design is 6CHI since the crystal with 4NKV presented differences in all the molecules analyzed since the oxidation state of the iron atom changes the molecule's orientation in the enzyme coupling. In contrast, in CYP21A2, no changes were observed. A greater biological congruence with 5BVU was observed because the coupling energies concur with the selectivity of the enzyme towards its endogenous substrates and reported inhibitors. It was concluded that the effect of the oxidation state of iron on the Binding Coupling Energy (BCE) depends directly on the functional groups attached to the steroidal molecule and their stereo-disposition.
{"title":"In Silico Approach: Effect of the Oxidation Iron State (Heme-Group) in Steroidogenesis Pathways","authors":"David Mora-Martinez, Jorge Organista-Nava, J. Sandoval-Ramírez, B. Illades-Aguiar, A. Carrasco-Carballo","doi":"10.33084/jmd.v2i1.3548","DOIUrl":"https://doi.org/10.33084/jmd.v2i1.3548","url":null,"abstract":"One of the main design features of enzyme regulators for the CYPs is the presence of a heme-group and different oxidation states in iron atoms. The selective inhibition of a CYP-enzyme can help to reduce the formation of steroidal molecules that causes undesirable disorders and is, therefore a topic of great biochemical-pharmaceutical interest. The present work carried out an analysis of effect on the coupling-energy of the iron core according to its changes from oxidation Fe(II) to Fe(III) state, over inhibitors and substrates, in a particular enzyme. Two crystals from CYP21A2, CYP11A1, CYP17A1 and CYP19A1 enzymes were selected, assigning the oxidation states separately in each case. It was highlighted that for CYP11A1 and CYP19A1 enzymes, no significant difference was observed in coupling energies between Fe oxidation state and crystal stereo-disposition. This last can be used to analyze their congruence towards the reported biological data. For CYP17A1, the ideal crystal for inhibitors design is 6CHI since the crystal with 4NKV presented differences in all the molecules analyzed since the oxidation state of the iron atom changes the molecule's orientation in the enzyme coupling. In contrast, in CYP21A2, no changes were observed. A greater biological congruence with 5BVU was observed because the coupling energies concur with the selectivity of the enzyme towards its endogenous substrates and reported inhibitors. It was concluded that the effect of the oxidation state of iron on the Binding Coupling Energy (BCE) depends directly on the functional groups attached to the steroidal molecule and their stereo-disposition.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81668844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. A. A. G. Arasi, Sapthasri Ravichandran, I. Iayaraman
COVID-19 pandemic has spread across the world in over 185 countries, with millions of infections and hundreds of thousands of deaths. The current pandemic has made the situation worse, forcing the development of better treatment. In this work, the binding ability of covid receptors with silymarin has been analyzed using AutoDock 1.4.6. Further, it is compared with the standard drug remdesivir. Silymarin, a potential phytochemical compound obtained from the seeds of the Silybum marianum (milk thistle) plant, has been documented as the antiviral agent against several viruses. So silymarin can also be an effective compound in the treatment of COVID-19. This study aims to determine the binding ability of COVID-19 receptors towards silymarin and further comparative analysis by remdesivir. Drug Discovery Studio version 2021 software was been used to analyse ligand and target. AutoDock 1.4.6 software was used to perform the docking study. Among the various receptors, 5N11 (Human beta1-coronavirus (β1CoV) OC43), 7MJP (SARS-CoV-2 receptor binding domain in complex with neutralizing antibody COVA2-39), 7JMO (SARS-CoV-2 receptor-binding domain in complex with neutralizing antibody COVA2-04) receptors showed the highest binding ability of -8.09, -7.23, -6.96 towards silymarin compared to the standard remdesivir having the docking score of -5.21, -3.76, -2.97, respectively. By the comparative analysis, silymarin has a better and highest binding ability.
{"title":"Comparative In-Silico Molecular Docking of Silymarin for SARS-CoV-2 Receptor","authors":"M. A. A. G. Arasi, Sapthasri Ravichandran, I. Iayaraman","doi":"10.33084/jmd.v2i1.3270","DOIUrl":"https://doi.org/10.33084/jmd.v2i1.3270","url":null,"abstract":"COVID-19 pandemic has spread across the world in over 185 countries, with millions of infections and hundreds of thousands of deaths. The current pandemic has made the situation worse, forcing the development of better treatment. In this work, the binding ability of covid receptors with silymarin has been analyzed using AutoDock 1.4.6. Further, it is compared with the standard drug remdesivir. Silymarin, a potential phytochemical compound obtained from the seeds of the Silybum marianum (milk thistle) plant, has been documented as the antiviral agent against several viruses. So silymarin can also be an effective compound in the treatment of COVID-19. This study aims to determine the binding ability of COVID-19 receptors towards silymarin and further comparative analysis by remdesivir. Drug Discovery Studio version 2021 software was been used to analyse ligand and target. AutoDock 1.4.6 software was used to perform the docking study. Among the various receptors, 5N11 (Human beta1-coronavirus (β1CoV) OC43), 7MJP (SARS-CoV-2 receptor binding domain in complex with neutralizing antibody COVA2-39), 7JMO (SARS-CoV-2 receptor-binding domain in complex with neutralizing antibody COVA2-04) receptors showed the highest binding ability of -8.09, -7.23, -6.96 towards silymarin compared to the standard remdesivir having the docking score of -5.21, -3.76, -2.97, respectively. By the comparative analysis, silymarin has a better and highest binding ability.","PeriodicalId":16421,"journal":{"name":"Journal of Molecular Docking","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74590329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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