cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.23565811.v1
title: Anti-aging activity of Syn-Ake peptide by <i>in silico</i> approaches and <i>in vitro</i> tests

description: The increase in the aging population worldwide has led scientists to turn to research to prevent the aging process. In this context, synthetic peptides emerge as candidate molecules for developing new anti-aging products. This study aims to investigate the possible interactions of Syn-Ake, a synthetic peptide, with matrix metalloproteinases (MMPs) and Sirtuin 1 (SIRT1), which are the targets of anti-aging activities with <i>in silico</i> approaches, and to determine the antioxidant activity, and safety profile of the peptide by <i>in vitro</i> methods such as cytotoxicity (MTT) and genotoxicity (Ames) tests. The molecular docking study showed that the docking score energy of MMP receptors was in the order of MMP-13 &lt; MMP-8 &lt; MMP-1. Syn-Ake peptide provided the lowest and the most stable binding to the SIRT1 receptor at −9.32 kcal/mol. Binding interaction and protein-ligand stability of Syn-Ake with MMPs and SIRT1 in a dynamic system were predicted by 50 ns molecular dynamic (MD) simulation studies. The MD results showed that the Syn-Ake peptide remained stable in the active site of MMP-13 and SIRT1 receptors during 50 ns simulations. In addition, the antioxidant activity of Syn-Ake was investigated using diphenyl-2-picril-hydrazine (DPPH) method since it is crucial to remove free radicals that are effective in skin aging. The results revealed the concentration-dependent increased DPPH radical scavenging activity of the peptide. Finally, the safety of the Syn-Ake was investigated, and the safe dose of the peptide was determined. In conclusion, <i>in silico</i> and <i>in vitro</i> analyses show that the Syn-Ake peptide may hold promise in anti-aging formulations with its high efficacy and safety profile. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23565811
title: Anti-aging activity of Syn-Ake peptide by <i>in silico</i> approaches and <i>in vitro</i> tests

description: The increase in the aging population worldwide has led scientists to turn to research to prevent the aging process. In this context, synthetic peptides emerge as candidate molecules for developing new anti-aging products. This study aims to investigate the possible interactions of Syn-Ake, a synthetic peptide, with matrix metalloproteinases (MMPs) and Sirtuin 1 (SIRT1), which are the targets of anti-aging activities with <i>in silico</i> approaches, and to determine the antioxidant activity, and safety profile of the peptide by <i>in vitro</i> methods such as cytotoxicity (MTT) and genotoxicity (Ames) tests. The molecular docking study showed that the docking score energy of MMP receptors was in the order of MMP-13 &lt; MMP-8 &lt; MMP-1. Syn-Ake peptide provided the lowest and the most stable binding to the SIRT1 receptor at −9.32 kcal/mol. Binding interaction and protein-ligand stability of Syn-Ake with MMPs and SIRT1 in a dynamic system were predicted by 50 ns molecular dynamic (MD) simulation studies. The MD results showed that the Syn-Ake peptide remained stable in the active site of MMP-13 and SIRT1 receptors during 50 ns simulations. In addition, the antioxidant activity of Syn-Ake was investigated using diphenyl-2-picril-hydrazine (DPPH) method since it is crucial to remove free radicals that are effective in skin aging. The results revealed the concentration-dependent increased DPPH radical scavenging activity of the peptide. Finally, the safety of the Syn-Ake was investigated, and the safe dose of the peptide was determined. In conclusion, <i>in silico</i> and <i>in vitro</i> analyses show that the Syn-Ake peptide may hold promise in anti-aging formulations with its high efficacy and safety profile. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23592975
title: Temperature effect in the inhibition of PLA<sub>2</sub> activity of <i>Bothrops brazili</i> venom by Rosmarinic and Chlorogenic acids, experimental and computational approaches

description: Myotoxicity caused by snakebite envenoming emerges as one of the main problems of ophidic accidents as it is not well neutralized by the current serum therapy. A promising alternative is to search for efficient small molecule inhibitors that can act against multiple venom components. Phospholipase A<sub>2</sub> (PLA<sub>2</sub>) is frequently found in snake venom and is usually associated with myotoxicity. Thus it represents an excellent target for the search of new treatments. This work reports the effect of temperature in the inhibition of catalytic properties of PLA<sub>2</sub> from <i>Bothrops brazili</i> venom by Rosmarinic (RSM) and Chlorogenic (CHL) acids through experimental and computational approaches. Three temperatures were evaluated (25, 37 and 50 °C). In the experimental section, enzymatic assays showed that RSM is a better inhibitor in all three temperatures. At 50 °C, the inhibition efficiency decayed significantly for both acids. Docking studies revealed that both ligands bind to the hydrophobic channel of the protein dimer where the phospholipid binds in the catalytic process, interacting with several functional residues. In this context, RSM presents better interaction energies due to stronger interactions with chain B of the dimer. Molecular dynamics simulations showed that RSM can establish selective interactions with ARG112B of PLA<sub>2</sub>, which is located next to residues of the putative Membrane Disruption Site in PLA2-like structures. The affinity of RSM and CHL acids towards PLA<sub>2</sub> is mainly driven by electrostatic interactions, especially salt bridge interactions established with residues ARG33B (for CHL) and ARG112B (RSM) and hydrogen bonds with residue ASP89A. The inability of CHL to establish a stable interaction with ARG112B was identified as the reason for its lower inhibition efficiency compared to RSM at the three temperatures. Furthermore, extensive structural analysis was performed to explain the lower inhibition efficiency at 50 °C for both ligands. The analysis performed in this work provides important information for the future design of new inhibitors. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23635464
title: Field-based 3D-QSAR for tyrosine protein kinase JAK-2 inhibitors

description: The present work aimed to develop a Field-based 3D-QSAR model with existing JAK-2 inhibitors. The JAK-STAT pathway is known to play a role in the development of autoimmune diseases, including rheumatoid arthritis, ulcerative colitis, and Crohn’s disease. Dysregulation of JAK-STAT is also linked to the development of myelofibrosis and other myeloproliferative diseases. JAK antagonists can be used in many areas of medicine. There are many compounds that already show inhibition of Jak-2. We have developed a Field-based 3D QSAR model which showed good correlation values (<i>r</i><sup>2</sup> 0.884 and <i>q</i><sup>2</sup> 0.67) with an external test set regression pred_<i>r</i><sup>2</sup> 0.562. Various properties, such as electronegativity, electro positivity, hydrophobicity, and shape features, were studied under the activity atlas to determine the inhibitory potential of ligands. These were also identified as important structural features responsible for biological activity. We performed virtual screening based on the pharmacophore features of the co-crystal ligand (PDB ID: 3KRR) and a dataset of NPS was selected with a RMSD value less than 0.8. The developed 3D QSAR model was used to screen ligands and calculate the predicted JAK-2 inhibition activity (pKi). The results of the virtual screening were validated using molecular docking and molecular dynamics simulations. SNP1 (SN00154718) and SNP2 (SN00213825) showed binding affinity of −11.16 and −11.08 kcal/mol, respectively, which were very close to the crystal ligand of 3KRR, −11.67 kcal/mol. The RMSD plot of the protein-ligand complex of SNP1 and 3KRR showed stable interactions with an average RMSD of 2.89 Å. Thus, a statistically robust 3D QSAR model could reveal more inhibitors and aid in the design of novel JAK-2 inhibitors.
DOI: 10.6084/m9.figshare.23635464.v1
title: Field-based 3D-QSAR for tyrosine protein kinase JAK-2 inhibitors

description: The present work aimed to develop a Field-based 3D-QSAR model with existing JAK-2 inhibitors. The JAK-STAT pathway is known to play a role in the development of autoimmune diseases, including rheumatoid arthritis, ulcerative colitis, and Crohn’s disease. Dysregulation of JAK-STAT is also linked to the development of myelofibrosis and other myeloproliferative diseases. JAK antagonists can be used in many areas of medicine. There are many compounds that already show inhibition of Jak-2. We have developed a Field-based 3D QSAR model which showed good correlation values (<i>r</i><sup>2</sup> 0.884 and <i>q</i><sup>2</sup> 0.67) with an external test set regression pred_<i>r</i><sup>2</sup> 0.562. Various properties, such as electronegativity, electro positivity, hydrophobicity, and shape features, were studied under the activity atlas to determine the inhibitory potential of ligands. These were also identified as important structural features responsible for biological activity. We performed virtual screening based on the pharmacophore features of the co-crystal ligand (PDB ID: 3KRR) and a dataset of NPS was selected with a RMSD value less than 0.8. The developed 3D QSAR model was used to screen ligands and calculate the predicted JAK-2 inhibition activity (pKi). The results of the virtual screening were validated using molecular docking and molecular dynamics simulations. SNP1 (SN00154718) and SNP2 (SN00213825) showed binding affinity of −11.16 and −11.08 kcal/mol, respectively, which were very close to the crystal ligand of 3KRR, −11.67 kcal/mol. The RMSD plot of the protein-ligand complex of SNP1 and 3KRR showed stable interactions with an average RMSD of 2.89 Å. Thus, a statistically robust 3D QSAR model could reveal more inhibitors and aid in the design of novel JAK-2 inhibitors.
DOI: 10.6084/m9.figshare.23592975.v1
title: Temperature effect in the inhibition of PLA<sub>2</sub> activity of <i>Bothrops brazili</i> venom by Rosmarinic and Chlorogenic acids, experimental and computational approaches

description: Myotoxicity caused by snakebite envenoming emerges as one of the main problems of ophidic accidents as it is not well neutralized by the current serum therapy. A promising alternative is to search for efficient small molecule inhibitors that can act against multiple venom components. Phospholipase A<sub>2</sub> (PLA<sub>2</sub>) is frequently found in snake venom and is usually associated with myotoxicity. Thus it represents an excellent target for the search of new treatments. This work reports the effect of temperature in the inhibition of catalytic properties of PLA<sub>2</sub> from <i>Bothrops brazili</i> venom by Rosmarinic (RSM) and Chlorogenic (CHL) acids through experimental and computational approaches. Three temperatures were evaluated (25, 37 and 50 °C). In the experimental section, enzymatic assays showed that RSM is a better inhibitor in all three temperatures. At 50 °C, the inhibition efficiency decayed significantly for both acids. Docking studies revealed that both ligands bind to the hydrophobic channel of the protein dimer where the phospholipid binds in the catalytic process, interacting with several functional residues. In this context, RSM presents better interaction energies due to stronger interactions with chain B of the dimer. Molecular dynamics simulations showed that RSM can establish selective interactions with ARG112B of PLA<sub>2</sub>, which is located next to residues of the putative Membrane Disruption Site in PLA2-like structures. The affinity of RSM and CHL acids towards PLA<sub>2</sub> is mainly driven by electrostatic interactions, especially salt bridge interactions established with residues ARG33B (for CHL) and ARG112B (RSM) and hydrogen bonds with residue ASP89A. The inability of CHL to establish a stable interaction with ARG112B was identified as the reason for its lower inhibition efficiency compared to RSM at the three temperatures. Furthermore, extensive structural analysis was performed to explain the lower inhibition efficiency at 50 °C for both ligands. The analysis performed in this work provides important information for the future design of new inhibitors. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23565812
title: <i>In silico</i>-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1

description: The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has led to over 600 million cases of coronavirus disease 2019 (COVID-19). Identifying effective molecules that can counteract the virus is imperative. SARS-CoV-2 macrodomain 1 (Mac1) represents a promising antiviral drug target. In this study, we predicted potential inhibitors of SARS-CoV-2 Mac1 from natural products using <i>in silico</i>-based screening. Based on the high-resolution crystal structure of Mac1 bound to its endogenous ligand ADP-ribose (ADPr), we first performed a docking-based virtual screening of Mac1 inhibitors against a natural product library and obtained five representative compounds (MC1–MC5) by clustering analysis. All five compounds were stably bound to Mac1 during 500 ns long molecular dynamics simulations. The binding free energy of these compounds to Mac1 was calculated using molecular mechanics generalized Born surface area and further refined with localized volume-based metadynamics. The results demonstrated that both MC1 (−9.8 ± 0.3 kcal/mol) and MC5 (−9.6 ± 0.3 kcal/mol) displayed more favorable affinities to Mac1 with respect to ADPr (−8.9 ± 0.3 kcal/mol), highlighting their potential as potent SARS-CoV-2 Mac1 inhibitors. Overall, this study provides potential SARS-CoV-2 Mac1 inhibitors, which may pave the way for developing effective therapeutics for COVID-19. Communicated by Ramaswamy H. Sarma Mac1 is a promising anti-SARS-CoV-2 therapeutic target. Virtual screening of natural products targeting SARS-CoV-2 Mac1 was performed against a library containing 282,192 compounds. Two potential Mac1 inhibitors were theoretically identified with more favorable affinities than the endogenous ligand ADPr.
DOI: 10.6084/m9.figshare.23565812.v1
title: <i>In silico</i>-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1

description: The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has led to over 600 million cases of coronavirus disease 2019 (COVID-19). Identifying effective molecules that can counteract the virus is imperative. SARS-CoV-2 macrodomain 1 (Mac1) represents a promising antiviral drug target. In this study, we predicted potential inhibitors of SARS-CoV-2 Mac1 from natural products using <i>in silico</i>-based screening. Based on the high-resolution crystal structure of Mac1 bound to its endogenous ligand ADP-ribose (ADPr), we first performed a docking-based virtual screening of Mac1 inhibitors against a natural product library and obtained five representative compounds (MC1–MC5) by clustering analysis. All five compounds were stably bound to Mac1 during 500 ns long molecular dynamics simulations. The binding free energy of these compounds to Mac1 was calculated using molecular mechanics generalized Born surface area and further refined with localized volume-based metadynamics. The results demonstrated that both MC1 (−9.8 ± 0.3 kcal/mol) and MC5 (−9.6 ± 0.3 kcal/mol) displayed more favorable affinities to Mac1 with respect to ADPr (−8.9 ± 0.3 kcal/mol), highlighting their potential as potent SARS-CoV-2 Mac1 inhibitors. Overall, this study provides potential SARS-CoV-2 Mac1 inhibitors, which may pave the way for developing effective therapeutics for COVID-19. Communicated by Ramaswamy H. Sarma Mac1 is a promising anti-SARS-CoV-2 therapeutic target. Virtual screening of natural products targeting SARS-CoV-2 Mac1 was performed against a library containing 282,192 compounds. Two potential Mac1 inhibitors were theoretically identified with more favorable affinities than the endogenous ligand ADPr.
DOI: 10.6084/m9.figshare.23643247
title: A multitier virtual screening study of phytoconstituents as Myeloid Cell Leukemias 1 inhibitors

description: Myeloid Cell Leukemia 1 (MCL1) is an anti-apoptotic protein that plays a critical role in regulating cell survival, particularly in cancer cells. It is a member of the BCL-2 family of proteins, which control the intrinsic pathway of apoptosis. MCL1 has emerged as a promising target for cancer therapy because it is overexpressed in a wide range of cancers, including breast, lung, prostate, and hematologic malignancies. Due to its remarkable role in cancer progression, it has been reflected as a promising drug target for cancer therapy. A few MCL1 inhibitors have been identified previously, but further research is needed to develop novel, effective and safe MCL1 inhibitors that can overcome resistance mechanisms and minimize toxicity in normal cells. In this study, we aim to search for compounds that target the critical binding site of MCL1 from phytoconstituent library from the IMPPAT database. To accomplish this, a multitier virtual screening approach involving molecular docking and molecular dynamics simulations (MDS) were used to evaluate their suitability for the receptor. Notably, certain screened phytoconstituents have appreciable docking scores and stable interactions toward the binding pocket of MCL1. The screened compounds underwent ADMET and bioactivity analysis to establish their anticancer properties. One phytoconstituent, Isopongaflavone, was identified that exhibiting higher docking and drug-likeness than the already reported MCL1 inhibitor, Tapotoclax. Isopongaflavone and and Tapotoclax, along with MCL1, were subjected to 100 nanoseconds (ns) MDS study to verify their stability inside the binding site of MCL1. The MDS findings demonstrated a strong binding affinity between Isopongaflavone and the MCL1 binding pocket, resulting in reduced conformational fluctuations. This investigation proposes Isopongaflavone as a promising candidate for the development of innovative anticancer therapeutics, pending the necessary validation procedures. Also, the findings provide valuable information for designing MCL1 inhibitors based on the protein’s structure. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23684913
title: Development, validation and analysis of a human profurin 3D model using comparative modeling and molecular dynamics simulations

description: The emergence of new viruses can lead to the outbreak of pandemics as occurred at the end of 2019 with the coronavirus disease (or COVID-19). The fastest way to effectively control viral infections is to develop broad-spectrum antivirals that can fight at least an entire class of viruses. Profurin, the furin precursor propeptide, is responsible for the autoactivation step which is crucial for the maturation of several viral substrates. This role makes the study of furin and profurin interactions interesting for the development of new potential broad-spectrum antivirals for the treatment against several human viral diseases. Since there is no 3D model of profurin published in the literature or deposited in a database, this work reports the development, validation and analysis of a profurin 3D model using comparative modeling and molecular dynamics. The model is available in ModelArchive at https://www.modelarchive.org/doi/10.5452/ma-ct8l7. The usage of this model will make possible further studies of molecular docking and MD simulations of the profurin-furin system, in the design of new potential broad-spectrum antivirals for the treatment against several human viral diseases. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23684913.v1
title: Development, validation and analysis of a human profurin 3D model using comparative modeling and molecular dynamics simulations

description: The emergence of new viruses can lead to the outbreak of pandemics as occurred at the end of 2019 with the coronavirus disease (or COVID-19). The fastest way to effectively control viral infections is to develop broad-spectrum antivirals that can fight at least an entire class of viruses. Profurin, the furin precursor propeptide, is responsible for the autoactivation step which is crucial for the maturation of several viral substrates. This role makes the study of furin and profurin interactions interesting for the development of new potential broad-spectrum antivirals for the treatment against several human viral diseases. Since there is no 3D model of profurin published in the literature or deposited in a database, this work reports the development, validation and analysis of a profurin 3D model using comparative modeling and molecular dynamics. The model is available in ModelArchive at https://www.modelarchive.org/doi/10.5452/ma-ct8l7. The usage of this model will make possible further studies of molecular docking and MD simulations of the profurin-furin system, in the design of new potential broad-spectrum antivirals for the treatment against several human viral diseases. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23643247.v1
title: A multitier virtual screening study of phytoconstituents as Myeloid Cell Leukemias 1 inhibitors

description: Myeloid Cell Leukemia 1 (MCL1) is an anti-apoptotic protein that plays a critical role in regulating cell survival, particularly in cancer cells. It is a member of the BCL-2 family of proteins, which control the intrinsic pathway of apoptosis. MCL1 has emerged as a promising target for cancer therapy because it is overexpressed in a wide range of cancers, including breast, lung, prostate, and hematologic malignancies. Due to its remarkable role in cancer progression, it has been reflected as a promising drug target for cancer therapy. A few MCL1 inhibitors have been identified previously, but further research is needed to develop novel, effective and safe MCL1 inhibitors that can overcome resistance mechanisms and minimize toxicity in normal cells. In this study, we aim to search for compounds that target the critical binding site of MCL1 from phytoconstituent library from the IMPPAT database. To accomplish this, a multitier virtual screening approach involving molecular docking and molecular dynamics simulations (MDS) were used to evaluate their suitability for the receptor. Notably, certain screened phytoconstituents have appreciable docking scores and stable interactions toward the binding pocket of MCL1. The screened compounds underwent ADMET and bioactivity analysis to establish their anticancer properties. One phytoconstituent, Isopongaflavone, was identified that exhibiting higher docking and drug-likeness than the already reported MCL1 inhibitor, Tapotoclax. Isopongaflavone and and Tapotoclax, along with MCL1, were subjected to 100 nanoseconds (ns) MDS study to verify their stability inside the binding site of MCL1. The MDS findings demonstrated a strong binding affinity between Isopongaflavone and the MCL1 binding pocket, resulting in reduced conformational fluctuations. This investigation proposes Isopongaflavone as a promising candidate for the development of innovative anticancer therapeutics, pending the necessary validation procedures. Also, the findings provide valuable information for designing MCL1 inhibitors based on the protein’s structure. Communicated by Ramaswamy H. Sarma