A Novel Pharmacophore Model to Identify Leads for Simultaneous Inhibition of Anti‐coagulation and Anti‐inflammatory Activities of Snake Venom Phospholipase A2 (original) (raw)
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Journal of Molecular Modeling
Snake venom, particularly of vipers from the Indian subcontinent, contains Phospholipase A2 (PLA2) as one its constituents which is widely implicated in hemorrhagic, cardiac arrest and death. Development of inhibitors of the protein can facilitate the weakening or annihilation of the venom toxicity and save many human lives. In the present communication, our studies relate to the design and development of structure-based ligands as inhibitors of PLA2 of Viper venom. The study involves the computational approach towards evaluating a library of molecules comprising of natural products, and synthetic molecules through docking studies on the venom protein PDB ID: 1OXL (a dimer, available in the literature). In silico experiments have resulted in the identification of several of them as PLA2 inhibitors. The inhibitory effect of PLA2 by these compounds is attributed to a great extent to their interaction with the residues Phe 46 and Val47 of chain B of the target protein and hence these two residues are identified as the key contributor for the said activity. In order to validate the in silico findings, a selected panel of compounds have been tested by in vitro and in vivo experiments against the venom, which has led to the observance of significant corroboration between the wet lab and in silico findings, validating thereby the in silico approach used in the present study. Figure Interaction of the potent inhibitor with PLA2
Journal of Biomolecular Structure and Dynamics, 2019
Snake venom of Naja naja comprises of several types of enzymes, and among them, water-soluble proteolytic enzyme, phospholipase A2 (PLA 2), is noteworthy for its numerous adverse effects, such as; cytotoxicity, cardiotoxicity, haemolytic, anti-coagulant, and hypotensive effects, including being highly potent as a neurotoxin. Limited anti-venom therapy (with their lower efficacy) has attracted considerable pharmacological interest to develop potent inhibitors of PLA 2. Thus, 34 experimentally proven and diverse synthetic inhibitors of PLA 2 were screened primarily on the basis of Glide extra precision docking and MM-GBSA rescoring function. Then, ten potential hits were subjected to induced fit docking, in which top three potential inhibitors were considered, and those were found to interact with Ca 2+ , disulfide binding site, and phosphatidylcholine activation sites, thereby, possibly disrupting the catalytic activity of Ca 2+ as well as the inflammatory functions of PLA 2. These compounds showed positive remarks on various physiochemical properties and pharmacologically relevant descriptors. Gap energy and thermodynamic properties were investigated by employing density functional theory for all compounds to understand their chemical reactivity and thermodynamic stability. Molecular dynamics simulation was performed for 100ns in order to evaluate the stability and binding modes of docked complexes, and the energy of binding was calculated through MM-PBSA analysis. On the whole, the proposed compounds could be used for targeted inhibition.
International Journal of Biological Macromolecules, 2019
Phospholipase A2 (PLA2) is the main constituent of snake venom. PLA2 enzymes catalyze the Ca2+ dependent hydrolysis of 2-acyl ester bonds of 3-sn-phospholipids, releasing fatty acids and lysophospholipids. Inside the body of the victim, PLA2 from snake venom induces either direct or indirect pathophysiological effects, including anticoagulant, inflammatory, neurotoxic, cardiotoxic, edematogenic, and myotoxic activities. Therefore, there is a need to find the potential inhibitors against PLA2 responsible for snakebite. In this study, we employed in silico and in vitro methods to identify the potential inhibitor against PLA2. Virtual screening and molecular docking studies were performed to find potent inhibitor against PLA2 using Traditional Chinese Medicine Database (TCM). Based on these studies, Scutellarin (TCM3290) was selected and calculated by density functional theory calculation at B3LYP/6-31G**++ level to explore the stereo-electronic features of the molecule. Further, minocycline was carried out by molecular docking study and DFT calculations. Quantum polarized ligand docking was performed to optimize the geometry of the protein–ligand complex. The protein–ligand complexes were carried out by binding free energy calculation and molecular dynamics (MD) simulation. The residence time of a protein-ligand complex is a critical parameter affecting natural influences in vitro. It is nonetheless a challenging errand to expect, regardless of the accessibility of incredible PC assets and a large variety of computing procedures. In this metadynamics situation, we used the conformational flooding technique to deal with rank inhibitors constructions. The systematic free energy perturbation (FEP) protocol and calculate the energy of both complexes. Finally, the selected compound of TCM3290 was studied in vitro analysis such as inhibition of PLA2 activity, hyaluronidase activity and fibrinogenolytic activity. The TCM3290 had a more binding affinity compare to minocycline, and interacted with the key residues of TYR63 and GLY31. DFT represented the highest HOMO and LUMO energy of 0.15146 eV. MD simulation with 100 ns proved that an inhibitor binding mode is more stable inside the binding site of PLA2. In vitro analysis shows that TCM3290 significantly neutralized by PLA2. The above observations confirmed that Scutellarin had a potent snake venom neutralizing capacity and could hypothetically be used for therapeutic drives of snakebite envenomation.
Toxins, 2017
Human phospholipase A₂ (hPLA₂) of the IIA group (HGIIA) catalyzes the hydrolysis of membrane phospholipids, producing arachidonic acid and originating potent inflammatory mediators. Therefore, molecules that can inhibit this enzyme are a source of potential anti-inflammatory drugs, with different action mechanisms of known anti-inflammatory agents. For the study and development of new anti-inflammatory drugs with this action mechanism, snake venom PLA₂ (svPLA₂) can be employed, since the svPLA₂ has high similarity with the human PLA₂ HGIIA. Despite the high similarity between these secretory PLA₂s, it is still not clear if these toxins can really be employed as an experimental model to predict the interactions that occur with the human PLA₂ HGIIA and its inhibitors. Thus, the present study aims to compare and evaluate, by means of theoretical calculations, docking and molecular dynamics simulations, as well as experimental studies, the interactions of human PLA₂ HGIIA and two svPLA₂...
Journal of Biomolecular Structure and Dynamics, 2014
Snake venom metalloproteinase (SVMP) (Echis coloratus (Carpet viper) is a multifunctional enzyme that is involved in producing several symptoms that follow a snakebite, such as severe local hemorrhage, nervous system effects and tissue necrosis. Because the three-dimensional (3D) structure of SVMP is not known, models were constructed, and the best model was selected based on its stereo-chemical quality. The stability of the modeled protein was analyzed through molecular dynamics (MD) simulation studies. Structure-based virtual screening was performed, and 15 potential molecules with the highest binding energies were selected. Further analysis was carried out with induced fit docking, Prime/MM-GBSA (ΔG Bind calculations), quantum-polarized ligand docking, and density functional theory calculations. Further, the stability of the lead molecules in the SVMP-active site was examined using MD simulation. The results showed that the selected lead molecules were highly stable in the active site of SVMP. Hence, these molecules could potentially be selective inhibitors of SVMP. These lead molecules can be experimentally validated, and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for snake antivenom.
Molecular Docking in Drug Discovery: A Review on Anti-snake Venom Development
International Journal of Biochemistry Research & Review, 2020
Snakebite is a frequent accident faced by rural community's dwellers, and it has remained a neglected public health problem in many countries. Snake venom is a complex mixture of proteins, and they participate to envenomation through a diverse array of bioactivities, such as bleeding, inflammation, and pain, cytotoxic, cardiotoxic or neurotoxic effects. The only approved and accepted treatment for snakebite envenoming is the use of antivenoms produced by the purification of IgG immunoglobulins immunized against specific snake venom. However, various technological approaches are being pursued by different research groups, including the use of small-molecule inhibitors, antibody-based bio-therapeutics and peptide-based aptamer against enzymatic toxins and non-enzymatic toxins in snake venom. Modern bioinformatics tools have been recently developed to mine snake venoms, helping focus experimental research on the most potentially interesting toxins. Some computational techniques pred...
In-Silico Drug Designing Through Protein-Ligand Interaction Studies Of Snake Venom Peptides
Toxins have evolved in plants, animals and microbes multiple times as part of defensive and/or prey capture strategies. Peptide toxins are usually found in animal venom. Most venom comprises a highly complex mixture of peptides, often with diverse and selective pharmacology. The source of peptide is specifically snake venom which is usually neurotoxins. We have selected four peptides Aggretin, Crotamine, Mambalgin, Myotoxin. In-silico drug design is crucial step to reduce the number of steps in drug designing process. The present study was focused to design a drug for snake venom peptides. The peptides are causative proteins for diseases like blood clotting, necrosis, acute renal failure, and anaphylaxis. The peptide structure was retrieved from Uniprot database and multiple sequence alignment was performed on the retrieved sequences using Clustal W. Rasmol software was used for protein visualization. Pubchem database was used for screening the chemical ligands. The chemical structure of selected ligands was obtained from Dundee pro drg server. The ligands were screened based on log P value for selection of better ligands which was used for docking studies. Docking was performed to find the inhibition activity against snake venom using HEX software. Autodocking was done using vina for different conformations of ligand.
In-Silico Drug Design through Protein-Ligand Interaction Studies of Snake Venom Peptides
In-silico drug design is crucial step to reduce the number of steps in drug designing process. The present study was focused to design a drug for snake venom peptides. We have selected a peptide Aggretin from the species Calloselasma rhodostoma, commonly known as Malayan pit-viper. The peptide structure was retrieved from Uniprot database and multiple sequence alignment was performed on the retrieved sequences using Clustal W. Rasmol software was used for protein visualization. Pubchem database was used for screening the chemical ligands. The chemical structure of selected ligands was obtained from Dundee pro drg server. The ligands were screened based on log P value for selection of better ligands which was used for docking studies. Docking was performed to find the inhibition activity against snake venom using HEX software. Highest negativity of E-value was shown by Aggretin peptide with Ellagic Acid ligand -232.51. Vibrational analysis was performed to check the energy changes and it was found that the energy of docking in case of Hex after vibrational analysis was higher.
Computational model for lipid binding regions in phospholipase (Ves a 1) from Vespa venom
Scientific Reports
The Thai banded tiger wasp (Vespa affinis) is a dangerous vespid species found in Southeast Asia, and its stings often result in fatalities due to the presence of lethal phospholipase A$$_{1}$$ 1 , known as Vespapase or Ves a 1. Developing anti-venoms for Ves a 1 using chemical drugs, such as chemical drug guide, remains a challenging task. In this study, we screened 2056 drugs against the opening conformation of the venom using the ZINC 15 and e-Drug 3D databases. The binding free energy of the top five drug candidates complexed with Ves a 1 was calculated using 300-ns-MD trajectories. Our results revealed that voxilaprevir had a higher binding free energy at the catalytic sites than other drug candidates. Furthermore, the MD simulation results indicated that voxilaprevir formed stable conformations within the catalytic pocket. Consequently, voxilaprevir could act as a potent inhibitor, opening up avenues for the development of more effective anti-venom therapeutics for Ves a 1.