Investigation of natural compounds as methyltransferase inhibitors against dengue virus: an in silico approach.

The global challenge posed by Dengue virus (DENV) infection persists, exacerbated by the absence of specific antiviral therapies. The viral methyltransferase (MTase) enzyme, crucial for viral RNA methylation and immune system evasion, has emerged as a promising drug target for combating Dengue fever. In this study, a comprehensive exploration of natural compounds derived from the COCONUT database was conducted, selecting 224 compounds based on their structural similarity to the native substrate of the MTase enzyme, S-adenosyl-L-methionine (SAM). Employing virtual screening techniques, four natural compounds (CNP0307160, CNP0082902, CNP0449158, and CNP0296775) with acceptable docking scores were selected for further re-docking after geometry optimization by the DFT method. Re-docking analyses unveiled significant interactions, including hydrogen bonds and hydrophobic interactions, between these selected ligands and the MTase protein. To gain deeper insights into the dynamic stability of these complexes, we conducted molecular dynamics simulations which showed lower RMSD values for CNP0307160, CNP0082902, and CNP0296775 when compared to the reference molecule. Furthermore, we assessed the structural and dynamic stability of the protein-ligand complexes through free binding energy calculations and Principal Component Analysis (PCA) of the simulation trajectories. In these analyses, the CNP0296775 compound exhibited promising results compared to the other three compounds. The cumulative findings of these investigations underscore the potential of CNP0296775 as a strong inhibitor of DENV MTase, thus offering a promising starting point for its further experimental validation and optimization.Communicated by Ramaswamy H. Sarma.

Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease.

The monkeypox virus (MPXV) is an enveloped, double-stranded DNA virus belonging to the genus Orthopox viruses. In recent years, the virus has spread to countries where it was previously unknown, turning it into a worldwide emergency for public health. This study employs a structural-based drug design approach to identify potential inhibitors for the core cysteine proteinase of MPXV. During the simulations, the study identified two potential inhibitors, compound CHEMBL32926 and compound CHEMBL4861364, demonstrating strong binding affinities and drug-like properties. Their docking scores with the target protein were -10.7 and -10.9 kcal/mol, respectively. This study used ensemble-based protein-ligand docking to account for the binding site conformation variability. By examining how the identified inhibitors interact with the protein, this research sheds light on the workings of the inhibitors' mechanisms of action. Molecular dynamic simulations of protein-ligand complexes showed fluctuations from the initial docked pose, but they confirmed their binding throughout the simulation. The MMGBSA binding free energy calculations for CHEMBL32926 showed a binding free energy range of (-9.25 to -9.65) kcal/mol, while CHEMBL4861364 exhibited a range of (-41.66 to -31.47) kcal/mol. Later, analogues were searched for these compounds with 70% similarity criteria, and their IC50 was predicted using pre-trained machine learning models. This resulted in identifying two similar compounds for each hit with comparable binding affinity for cysteine proteinase. This study's structure-based drug design approach provides a promising strategy for identifying new drugs for treating MPXV infections.

Computer-assisted discovery of safe and effective DprE1/ aaRSs Inhibitors against TB utilizing Drug Repurposing approach.

BACKGROUND: The emergence of various drug-resistant strains of Mycobacterium tuberculosis compelled medicinal chemists to expedite the discovery of novel, safer alternatives to present regimens. Decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1), an essential component of arabinogalactan biosynthesis, has been considered a novel target for developing new inhibitors against Tuberculosis. We aimed to discover DprE1 inhibitors utilizing the drug repurposing approach. METHODS: A structure-based virtual screening of FDA and world-approved drugs database was carried out, and initially, 30 molecules were selected based on their binding affinity. These compounds were further analyzed by molecular docking with extra-precision mode, MMGBSA binding free energy estimation, and prediction of ADMET profile. RESULTS: Based on the docking results and MMGBSA energy values- ZINC000006716957, ZINC000011677911, and ZINC000022448696 were identified to be the top three hit molecules with good binding interactions inside the active site of DprE1. These hit molecules were subjected to molecular dynamics (MD) simulation for a period of 100 ns to study the dynamic nature of the binding complex. MD results were in accordance with molecular docking and MMGBSA analysis showing protein-ligand contacts with key amino acid residues of DprE1. CONCLUSION: Based on their stability throughout the 100 ns simulation, ZINC000011677911 was the best in silico hit with an already known safety profile. This molecule could lead to future optimization and development of new DprE1 inhibitors.

QcrB inhibition as a potential approach for the treatment of tuberculosis: A review of recent developments, patents, and future directions.

The unmet medical need for drug-resistant tuberculosis (DRTB) is a significant concern. Accordingly, identifying new drug targets for tuberculosis (TB) treatment and developing new therapies based on these drug targets is one of the strategies to tackle DRTB. QcrB is an innovative drug target to create treatments for DRTB. This article highlights QcrB inhibitors and their therapeutic compositions for treating TB. The literature for this article was gathered from PubMed and free patent databases utilizing different keywords related to QcrB inhibitor-based inventions. The data was collected from the conceptualization of telacebec (2010) QcrB to December 2022. A little interesting and encouraging research has been performed on QcrB inhibitors. Telacebec and TB47 are established QcrB inhibitors in the clinical trial. The inventive QcrB inhibitor-based drug combinations can potentially handle DRTB and reduce the TB therapy duration. The authors anticipate great opportunities in fostering QcrB inhibitor-based patentable pharmaceutical inventions against TB. Drug repurposing can be a promising strategy to get safe and effective QcrB inhibitors. However, developing drug resistance, drug tolerance, and selectivity of QcrB inhibitors for Mtb will be the main challenges in developing effective QcrB inhibitors. In conclusion, QcrB is a promising drug target for developing effective treatments for active, latent, and drug-resistant TB. Many inventive and patentable combinations and compositions of QcrB inhibitors with other anti-TB drugs are anticipated as future treatments for TB.

Differences in structural elements of Bcr-Abl oncoprotein isoforms in Chronic Myelogenous Leukemia.

in silico modeling, using Psipred and ExPASy servers was employed to determine the structural elements of Bcr-Abl oncoprotein (p210(BCR-ABL)) isoforms, b2a2 and b3a2, expressed in Chronic Myelogenous Leukemia (CML). Both these proteins are tyrosine kinases having masses of 210-kDa and differing only by 25 amino acids coded by the b3 exonand an amino acidsubstitution (Glu903Asp). The secondary structure elements of the two proteins show differences in five α-helices and nine ß-strands which relates to differences in the SH3, SH2, SH1 and DNA-binding domains. These differences can result in different roles played by the two isoforms in mediating signal transduction during the course of CML.

Model of ß-Sheet of Muscle Fatty Acid Binding Protein of Locusta migratoria Displays Characteristic Topology.

The ß-sheet of muscle fatty acid binding protein of Locusta migratoria (Lm-FABP) was modeled by employing 2-D NMR data and the Rigid Body Assembly method. The model shows the ß-sheet to comprise ten ß-strands arranged anti-parallel to each other. There is a ß-bulge between Ser 13 and Gln 14 which is a difference from the published structure of ß-sheet of bovine heart Fatty Acid Binding Protein. Also, a hydrophobic patch consisting of Ile 45, Phe 51, Phe 64 and Phe 66 is present on the surface which is characteristic of most Fatty Acid Binding Proteins. A "gap" is present between ßD and ßE that provides evidence for the presence of a portal or opening between the polypeptide chains which allows ligand fatty acids to enter the protein cavity and bind to the protein.

A Structured-based Model for the Decreased Activity of Ala222Val and Glu429Ala Methylenetetrahydrofolate Reductase (MTHFR) Mutants.

The structure of human Methylenetetrahydrofolate Reductase (MTHFR) is not known either by NMR or by X-ray methods. Phosphorylation seems to play an important role in the functioning of this flavoprotein. MTHFR catalyzes an irreversible reaction in homocysteine metabolism. Phosphorylation decreases the activity of MTHFR by enhancing the sensitivity of the enzyme to SAdenosylmethione. Two common polymorphisms in MTHFR, Ala222Val and Glu429Ala, can result in a number of vascular diseases. Effects of the Glu429Ala polymorphism on the structure of human MTHFR remain undetermined due to limited structural information. Hence, structural models of the MTHFR mutants were constructed using I-TASSER and assessed by PROCHECK, DFIRE and Verify3D tools. A mechanism is further suggested for the decreased activity of the Ala222Val and Glu429Ala mutants due to a decrease in number of serine phosphorylation sites using information gleaned from the molecular models. This provides insights for the understanding of structure-function relationship for MTHFR.

Porphyrin derivatives as inhibitors for acetylcholinesterase from Drosophila melanogaster.

The cure for Alzheimer's disease (AD) is still unknown. According to Cholinergic hypothesis, Alzheimer's disease is caused by the reduced synthesis of the neurotransmitter, Acetylcholine. Regional cerebral blood flow can be increased in patients with Alzheimer's disease by Acetylcholinesterase (AChE) inhibitors. In this regard, Tetraphenylporphinesulfonate (TPPS), 5,10,15,20- Tetrakis (4-sulfonatophenyl) porphyrinato Iron(III) Chloride (FeTPPS) and 5,10,15,20-Tetrakis (4-sulfonatophenyl) porphyrinatoIron(III) nitrosyl Chloride (FeNOTPPS) were investigated as candidate compounds for inhibition of Acteylcholinesterase of Drosophila melanogaster (DmAChE) by use of Molecular Docking. The results show that FeNOTPPS forms the most stable complex with DmAChE.

Insight from γC1 protein model for implication in cotton leaf curl disease.

DNA γ is approximately half of the size of Begomovirus DNA. It encodes a γC1 gene that is conserved in position and size. This gene has the capacity to encode a 13 to 14 kDa protein comprising 118 amino acid residues. It has been shown earlier that γC1 protein is necessary for inducing symptoms of cotton leaf curl disease. The structure for γC1 (CLCuDγ01-Pakistan) is still unknown. Therefore, a model of γC1 (CLCuDγ01-Pakistan) was developed using DoBo and I-TASSER servers followed by validation by PROCHECK and VERIFY 3D servers. The developed model provides an insight in a role for this multifunctional protein in causing Cotton Leaf Curl Disease (CLCuD). A possible function of this protein might be the suppression of RNAsilencing in cotton plants.

Binding interactions of porphyrin derivatives with Ca(2+) ATPase of sarcoplasmic reticulum (SERCA1a).

The use of Porphyrin derivatives as photosensitizers in Photodynamic Therapy (PDT) was investigated by means of a molecular docking study. These molecules can bind to intracellular targets such as P-type CaCa(2+) ATPase of sarcoplasmic reticulum (SERCA1a). CAChe software was successfully employed for conducting the docking of Tetraphenylporphinesulfonate(TPPS), 5,10,15,20- Tetrakis (4-sulfonatophenyl) porphyrinato Iron(III) Chloride (FeTPPS) and 5,10,15,20-Tetrakis (4-sulfonatophenyl) porphyrinato Iron(III) nitrosyl Chloride (FeNOTPPS) with CaCa(2+) ATPase from sarcoplasmic reticulum of rabbit. The results show that FeNOTPPS forms the most stable complex with CaCa(2+) ATPase.