Binding Affinity Score Research Articles

The utilization of natural eco-benign sources for sustainable management to preserve hides and docking analysis of identified potential phytochemicals.

The industrial leather sector is one of the most ancient industries globally and continues to influence the global economic system in contemporary times significantly. Regardless of income, the leather sector is widely recognized as a significant environmentally detrimental sector because of the utilization of materials involved in preserving and processing leather. Raw hides, the primary ingredient in the leather industry, are highly susceptible to microbial attack once they have been flayed from animals. The current review provides information about the diverse operational processes employed in the beam house to produce leather goods. This paper primarily focuses on the preservation of various types of hides, including those derived from goats, cows, sheeps, deers, pigs, and other species, with particular emphasis on bio-based preservation methods. It also discusses various salt and salt-free curing methods along with their limitations. Furthermore, it reviews a viable and economically advantageous option for preserving animal hides using plant and microbial sources. Moreover, it focuses on investigating the molecular docking interactions between three critical enzymes in the phytochemical synthesis pathway, namely phenylalanine ammonia-lyase, phosphomevalonate kinase, and dihydroflavonol 4-reductase, and a set of specific modulators, followed by ADMET analyses. The objective was to determine the optimal binding affinity score for these enzyme-modulator complexes through virtual screening. The depiction of protein-ligand interactions offers potential benefits for future research endeavours, as well as valuable insights into the identification of modulators and the evaluation of the potency and efficacy of phytochemicals in the preservation of hides.

In silico Exploration on The Potency of Basil (Ocimum basilicum) as an Anti-Aging Skin Agent

New and improved skin care products and procedures have been established by technological advances and scientific investigation. By increasing the skin's moisture, firmness, and elasticity, anti-aging skin care can enhance the skin's overall condition. The objective of this study was to examine the potential of basil's chemical compounds as an in silicoanti-aging agent. Exploration of online databases, scholarly articles from national and international journals, and analysis using docking software are selected as examples of data collection methods. Matrix metalloproteinase 1 (MMP1), with PDB code 966C, is one of the targeted proteins related to skin anti-aging. Ladanein, acacetin, luteolin, 5-hydroxy-7,4'-dimethoxyflavone and genkwanin are five basil compounds that are predicted to exhibit anti-aging agents based on the presence of the binding affinity score indicator and the similarity of the appropriate attachment sites compared to the native ligand used. The scores for the binding affinity of luteolin, ladanein, acacetin, 5-hydroxy-7,4'-dimethoxyflavone, and genkwanin are -10, -9.9, -9.9, -9.8, and -9.6 kcal/mol, respectively. At the attachment positions of five basil compounds, the interactions with ASN 180, LEU 181 and ALA 182 key amino acids, which are the attachment sites for the native ligands, were also formed.

In Silico Study of Enzymatic Degradation of Bioplastic by Microalgae: An Outlook on Microplastic Environmental Impact Assessment, Challenges, and Opportunities.

Microplastics are tiny pieces of non-biodegradable plastic that can take thousands of years to break down. As microplastics degrade, they release harmful compounds into the environment, which can be found in the surroundings. The microplastics found in the environment are hard to detect and remove because of their small particle sizes. Microplastics cannot decompose naturally, so they accumulate in the environment and cause pollution. As a result, bioplastics can be produced from a vast array of substrates, including biopolymers, citrus peels, leather, and feather wastes. Blue-green microalgae namely Arthrospira platensis (spirulina) contains enzymes such as laccase and catalase which can be responsible for the degradation of bioplastics. In our study, we performed molecular docking to identify the binding affinities of different enzymes such as laccase and catalase with different substrates, focusing on determining the most suitable substrate for enhancing enzyme activity for degradation of bioplastics. The analysis revealed that veratryl alcohol is the most suitable substrate for laccase, whereas lignin is the more preferred substrate for catalase with the highest binding affinity score of -5.9 and -8.1kcal/mol. Moreover, degradation, challenges, opportunities, and applications of bioplastics in numerous domains such as cosmetics, electronics, agriculture, medical, textiles, and food industries have also been highlighted.

Detection and In Silico Study of Neochlorogenic Acid from Rhizophora apiculata Stem Bark Extract as HBV Replication Inhibitors

This study aims to detect and characterize the presence of neochlorogenic acid in Rhizophora apiculata stem bark extract and to examine its potential as an inhibitor of Hepatitis B virus (HBV) replication with in silico approach. This explorative descriptive study used liquid chromatography-mass spectrometry (LC-MS/MS) analysis to detect the content of neochlorogenic acid, and an in silico study through molecular docking analysis using the blind docking technique to test its potential to inhibit HBV replication. LCMS/MS results showed that the neochlorogenic acid was present in R. apiculata stem bark extract which was detected with a peak at 3.94 retention time, and fragment ion with a m/z value of 355.1029. The docking analysis results showed that neochlorogenic acid forms a binding site that is relatively similar to the reference ligand to the HBV capsid protein, involving amino acid residues PHE 23, PRO 25, PHE 110, TYR 118, TRP 102, ILE 139, LEU 140, and SER 141, with binding affinity score -6.3 kcal/mol. Therefore, based on the results of this study, it can be concluded that neochlorogenic acid derived from stem bark extract of R. apiculata has the potential to be used as an alternative treatment for hepatitis B virus infection.

Iterative machine learning-based chemical similarity search to identify novel chemical inhibitors

Machine learning-based chemical screening has made substantial progress in recent years. However, these predictions often have low accuracy and high uncertainty when identifying new active chemical scaffolds. Hence, a high proportion of retrieved compounds are not structurally novel. In this study, we proposed a strategy to address this issue by iteratively optimizing an evolutionary chemical binding similarity (ECBS) model using experimental validation data. Various data update and model retraining schemes were tested to efficiently incorporate new experimental data into ECBS models, resulting in a fine-tuned ECBS model with improved accuracy and coverage. To demonstrate the effectiveness of our approach, we identified the novel hit molecules for the mitogen-activated protein kinase kinase 1 (MEK1). These molecules showed sub-micromolar affinity (Kd 0.1–5.3 μM) to MEKs and were distinct from previously-known MEK1 inhibitors. We also determined the binding specificity of different MEK isoforms and proposed potential docking models. Furthermore, using de novo drug design tools, we utilized one of the new MEK inhibitors to generate additional drug-like molecules with improved binding scores. This resulted in the identification of several potential MEK1 inhibitors with better binding affinity scores. Our results demonstrated the potential of this approach for identifying novel hit molecules and optimizing their binding affinities.

Exploration of Potentially Bioactive Compounds from Fingerroot (Boesenbergia rotunda L.) as Inhibitor of Atherosclerosis-Related Proteins (CETP, ACAT1, OSC, sPLA2): An in silico Study

Boesenbergia rotunda L., commonly known as fingerroot, is recognized as one of Indonesia's medicinal plants with significant potential for treating various diseases, including atherosclerosis. This study aims to analyze the anti-atherosclerosis potential of bioactive compounds found in fingerroot by assessing their inhibitory effects on four proteins associated with atherosclerosis (CETP, ACAT1, OSC, and sPLA2). Bioactive compounds from B. rotunda were retrieved from the KnapSack database. The drug-likeness properties were predicted using the SwissADME web server, and the bioactivity of the compounds was assessed using the PASSOnline server. The identification of active sites on proteins and the validation of protein structures were performed using the SCFBio web server and Autodock Vina. Specific docking simulations between fingerroot compounds and the target proteins were carried out using AutoDock Vina. The analysis revealed that fingerroot contains 20 bioactive compounds with favorable drug-like properties. Among these, dihydrochrysin, sakuranetin, isopimaric acid, 2S-pinocembrin, 5,7-dihydroxy-8-C-geranylflavanone, 7,4'-dihydroxy-5-methoxyflavanone, and 5,7-dihydroxy-8,7-methoxy-5-hydroxy-8-geranylflavanone were predicted to exhibit anti-atherosclerosis activities. In the interactions with CETP, rubranine and (-)-4-hydroxypanduratin A showed the lowest binding affinity scores. Meanwhile, in interactions with ACAT1, OSC, and sPLA2, rubranine and 5,7-dihydroxy-8-C-geranylflavanone displayed the lowest binding affinities. In conclusion, fingerroot exhibits high potential as an anti-atherosclerosis agent through the inhibition of four proteins associated with atherosclerosis, as predicted through in silico analysis.

Cytotoxic Potential of Novel Quinoline Derivative: 11-(1,4-Bisaminopropylpiperazinyl)5-methyl-5H-indolo[2,3-b]quinoline against Different Cancer Cell Lines via Activation and Deactivation of the Expression of Some Proteins.

The current study evaluated the cytotoxic activity of 11-(1,4-bisaminopropylpiperazinyl)5-methyl-5H-indolo[2,3-b]quinoline (BAPPN), a novel derivative of 5-methyl-5H-indolo[2,3-b]quinoline, against hepatocellular carcinoma (HepG2), colon carcinoma (HCT-116), breast (MCF-7), and lung (A549) cancer cell lines and the possible molecular mechanism through which it exerts its cytotoxic activity. BAPPN was synthesized and characterized with FT-IR and NMR spectroscopy. The binding affinity scores of BAPPN for caspase-3 PDB: 7JL7 was -7.836, with an RMSD of 1.483° A. In silico screening of ADME properties indicated that BAPPN showed promising oral bioavailability records in addition to their high gastrointestinal absorption and blood-brain barrier penetrability. BAPPN induced cytotoxicity, with IC50 values of 3.3, 23, 3.1, and 9.96 μg/mL against cancer cells HepG2, HCT-116, MCF-7, and A549, respectively. In addition, it induced cell injury and morphological changes in ultracellular structure, including cellular delayed activity, vanishing of membrane blebbing, microvilli, cytoplasmic condensation, and shrunken nucleus with more condensed chromatin autophagosomes. Furthermore, BAPPN significantly increased the protein expression of caspase-3 and tumor suppressor protein (P53). However, it significantly reduced the secretion of vascular endothelial growth factor (VEGF) protein into the medium and decreased the protein expression of proliferation cellular nuclear antigen (PCNA) and Ki67 in HepG2, HCT-116, MCF-7, and A549 cells. This study indicates that BAPPN has cytotoxic action against liver, colon, breast, and lung cancer cell lines via the up-regulation of apoptotic proteins, caspase-3 and P53, and the downregulation of proliferative proteins, VEGF, PCNA, and Ki67.

Theoretical investigation, solvation effect, topology, NCI and molecular docking studies on potential Pemigatinib

The titled compound TA structure was optimized in B3LYP/cc-pVDZ basis set using Gaussian software. In natural bond orbital analysis the highest stabilization energy is 82.3 kcal/mol, which is confirmed by LP(1)-C19 to antibonding π*(C13-C14). Electron localization and delocalization areas are confirmed by wavefunction studies. The Gaussian-16w software establishes thermodynamic properties for a titled compound which is confirmed by various solvents. The HOMO and LUMO analysis ethanol have the highest energy gap value, which is 5.88 eV. In molecular electrostatic potential study nitrogen is the nucleophilic attack (blue color) and oxygen is the electrophilic attack (red color). In non-linear optical (NLO) study water solvent shows the highest dipole moment activity. The docking study showed the greatest binding affinity score of −4.08 kcal/mol.

Mechanisms of Nelumbinis folium targeting PPARγ for weight management: A molecular docking and molecular dynamics simulations study

The lotus leaf, Nelumbinis folium (NF), has frequently appeared in obesity clinical trials as an intervention to promote weight loss and improve metabolic profiles. However, the molecular mechanisms by which it interacts with important obesity targets and pathways, such as the peroxisome proliferator-activated receptor gamma (PPARγ) within the PPAR signalling pathway, were not well understood. This study aims to screen for candidate compounds from NF with desirable pharmacokinetic properties and examine their binding feasibility at the PPARγ ligand-binding domain (LBD). Ligand- and structure-based screening of NF compounds were performed, and a consensus approach has been applied to identify druggable candidates. By examining the pharmacokinetic profiles, a large proportion of NF compounds exhibited favourable drug-likeness and oral bioavailability properties. Furthermore, the binding affinity scores and poses provided new insights on the distinctive binding behaviours of NF compounds at the LBD of PPARγ in its inactive form. Several NF compounds could bind strongly to PPARγ at sub-pockets where partial agonists and antagonists were found to bind and may induce conformational changes that influence co-repressor binding, trans-repression, and gene expression inhibition. Subsequent molecular dynamics simulations of a candidate compound (NF129 narcissin) bound to PPARγ revealed conformational stability, residue fluctuation, and binding behaviours comparable to that of the known inhibitor, SR1664. Therefore, it can be proposed that narcissin exhibits characteristics of a PPARγ antagonist. Further experimental validation to support the development of NF129 as a future anti-obesity agent is warranted.

ADMET profiling and molecular docking of pyrazole and pyrazolines derivatives as antimicrobial agents

In the present study, a Molecular Docking and in silico ADMET analysis were performed to identify the possible inhibitory effect of 23 molecules, pyrazole and pyrazolines derivatives, on Escherichia coli and to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of all compounds. According to the results, every compound examined might bind to this bacterium's active site (PDB: 1FJ4). The results obtained in silico demonstrated that Only 4 (M6, M17, M19 and M20) of the 23 compounds were selected due to their inhibitory action and proximity to the important catalytic residues Thr302, Thr300, Val270, and His298 of the major protease and could be considered as orally active drug candidates due to their physical and chemical properties. The compounds M6, M17, M19 and M20 were subjected to Lipinski’s rule of five because it has the best binding affinity score in the binding study of the compound with the protein (-9.6, −9.3, −9.5, −10.3 Kcal/mol) successively. Pyrazole derivatives and the structure of pyrazolines are also effectively discussed in this paper for potential application as antibacterial agents due to their significant inhibitory activity. We were also able to predict a new potential inhibitor against a target of interest because to the result that we obtained.

Exploring EGFR inhibitors with the aid of virtual screening, docking, and dynamics simulation studies

In humans, Epidermal Growth Factor Receptor (EGFR) is linked to small-cell lung cancer, breast cancer, and glioblastoma. Receptor kinase inhibitors against EGFR have become a standard treatment option for non-small cell lung cancer (NSCLC), breast cancer patients, and even for those with EGFR mutations or resistance. About 2734 FDA-approved medication compounds were subjected to virtual screening for EGFR kinase inhibitory activity. The top 30 molecules were chosen based on the binding affinity scores and subjected to extra-precision docking and binding free energy analysis. The ADMET profile of the top three hit molecules was verified to confirm their druggability nature. Top three hits- compound 1047 (ZINC000001550477), 1302 (ZINC00003781952), and 2332 (ZINC000019632618) were identified on account of their MMGBSA binding affinity values. The top three hit compounds were subjected to molecular dynamics (MD) simulation for 100 ns. The dynamic nature of the ligand-protein complex was analyzed which corroborated the results of molecular docking and MMGBSA analysis studies. All the top three hits were further subjected to steered MD studies for testing the strength of these ligand-receptor binding in the presence of an external force. Compound 2332 (ZINC000019632618) was identified as the best hit molecule that can be used as a lead to develop newer derivatives of EGFR kinase inhibitors. Communicated by Ramaswamy H. Sarma

Theoretical Investigation on Solvents Effect in Molecular Structure (TD-DFT, MEP, HOMO-LUMO), Topological Analysis and Molecular Docking Studies of N-(5-((4-Ethylpiperazin-1-yl)Methyl)Pyridin-2-yl)-5-Fluoro-4-(4-Fluoro-1-Isopropyl-2-Methyl-1H-Benzo[d] Imidazol-6-yl) Pyrimidin-2-Amine

B3LYP/cc-pVDZ generated the best N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d] imidazol-6-yl) pyrimidin-2-amine (TA) results. The NBO study shows that the LP (1) N16 to π*(C17-N19) has the highest stabilization energy at 53.86 kcal/mol. Electron localization and delocalization areas are confirmed by wavefunction studies. The Gaussian-16w software establishes thermodynamic properties for a titled compound which is confirmed by various solvents. The frontier molecular orbital studies we confirmed by gas phase have the highest bond gap value which is 4.02 eV. The titled compound nitrogen is the nucleophilic attack (blue color) and oxygen is the electrophilic attack (red color), which is confirmed by MEP study. In non-linear optical (NLO) study water solvent shows the highest dipole moment activity, due to the solvent’s interaction the gas phase dipole moment is lower. The docking study showed the greatest binding affinity score of −5.28 kcal/mol.

Exploring the therapeutic potential of green tea phytocompounds for pancreatic cancer: An mRNA differential gene expression and pathway analysis study

Introduction and Aim: Pancreatic adenocarcinoma, which develops from the exocrine pancreas, is the most prevalent and aggressive type of pancreatic tumour having increased global prevalence, and has more than doubled over the 30 years. The aim of this study is to explore therapeutic potential of Camellia sinensis for pancreatic cancer using mRNA datasets and molecular docking technology. Materials and Methods: The purpose of the current study is to use computational methods to assess the effectiveness of several Camellia sinensis phytochemicals against Pancreatic cancer. The IMMPAT databank is utilized to retrieve the possible ligands. Molecular docking was methodically carried out using the virtual screening tool PyRx and the BIOVIA Discovery Studio Visualizer to forecast the binding affinity among the phytochemicals and the targeted proteins. Using ADMET filters, the ligands' pharmacological assessment was completed. Results: The fifty-two phytochemicals identified from Camellia sinensis were initially screened based on their affinity towards the targeted proteins. The ligand binding affinity score suggested that the phytochemical Vitamin E had the greater affinity towards the two targeted proteins and can be a promising therapeutic potential for the study of pancreatic cancer. Conclusion: The outcomes of this investigation suggested that the phytocompound Vitamin E, upon molecular docking exhibited the highest binding affinity which can be used as a drug candidate for pancreatic cancer.

Ensemble-based virtual screening of African natural products to target human thymidylate synthase

Human thymidylate synthase (hTS) is a validated drug target for chemotherapy. A virtual screening experiment was used to prioritize a list of compounds from African Natural Products Databases docked against the orthosteric binding pocket of hTS. Consensus scores of binding affinities from ensemble-based virtual screening, hydrated docking and MM-PBSA calculations ranked compounds NEA4433 and NEA4434 as the best candidates owing to binding affinity scores in the picomolar order, their excellent ADMET profiles and the good stability of the protein-ligand complexes formed. The current study demonstrates the role of water in small molecule binding to hTS in mediating protein-ligand interactions. Similarly, the robust ensemble docking (relaxed scheme complex) ranked NEA4433 and NEA4434 as the best candidates. Furthermore, the best candidates prioritized were shown to strongly interact with the same residues that interacted with hTS substrate and cofactor.

Structural, electronic features, photoluminescence property, antimicrobial activity and spectral properties of 5-bromosalicylaldehyde derivative

Infrared, ultraviolet, fluorescence, and NMR spectroscopy were used to characterize the synthesiszd Schiff base. Theoretically, this work is investigated with the DFT/B3LYP/cc-pVDZ. The DFT was applied in order determine the size, shape, and structure of the molecule. The Multiwfn-3.8 was used for topological studies, like ELF, LOL, ALIE, and RDG (non-covalent interaction). The TD-SCF method was used for theoretical UV–Visible spectral analysis. Two different peaks are presented in fluorescence spectra such as 498 nm and 646 nm. The HOMO-LUMO, MEP, MPA, NPA, NBO and NLO were all calculated with the same basis set level. The NBO analysis identify the inter and intra molecular bond properties. The Swiss ADMET online toll used for titled compound pharmacological properties. Antimicrobial activity shows titled compound moderate activity, when compared to standard. In docking study, the titled compound has highest binding affinity score.

Ugi efficient synthesis of novel N–alkylated lipopeptides, antimicrobial properties and computational studies in Staphylococcus aureus via MurD antibacterial target

Lipopeptides are medicinally essential building blocks with strong hemolytic, antifungal and antibiotic potential. In the present research article, we are presenting our findings regarding the synthesis of N–alkylated lipopeptides via Ugi four-component approach, their antimicrobial potential against pathogenic (Gram-positive and Gram-negative) bacteria, as well as computational studies to investigate the compounds binding affinity and dynamic behavior with MurD antibacterial target. Molecular docking demonstrated the compounds have good binding ability with MurD enzyme. The FT94, FT95 and FT97 compounds revealed binding affinity scores of −8.585 kcal mol− 1, −7.660 kcal mol− 1 and −7.351 kcal mol− 1, respectively. Furthermore, dynamics analysis pointed the systems high structure dynamics. The docking and simulation results were validated by binding free energies, demonstrating solid intermolecular interactions and in the assay in vitro, the Minimal Inhibitory Concentration (MIC) of FT97 to Staphylococcus aureus (S. aureus) was 62.5 μg/mL. In conclusion, a moderate inhibitory response of peptoid FT97 was observed against the Gram-positive bacteria, S. aureus and B. cereus.

Hecogenin a Plant Derived Small Molecule as an Antagonist to BACE-1: A Potential Target for Neurodegenerative Disorders.

The field of drug discovery has recognized the significance of computer-aided drug design. Recent advancements in structure identification and characterization, bio-computational science and molecular biology have significantly contributed to the development of novel treatments for various diseases. Alzheimer's disease is prevalent in over 50 million affected people, with the pathological condition of amyloidal plaque formation by the beta-amyloidal peptide that results in lesions of the patient's brain, thus making the target prediction and treatment a hurdle. In this study, we evaluated the potential of 54 bioactive compounds from Justicia adhatoda L. and Sida cordifolia L. identified through LC-MS/MS against the β-site amyloid precursor cleaving enzyme (beta-secretase) that results in the formation of amyloidal plaques. To study the drug-likeness of the phytocompounds, Lipinski's rule of five for ADME profiling and toxicity prediction was performed. Molecular docking was performed using auto-dock tool of PyRx software; molecular dynamic simulations were performed using the Schrodinger suite. Molecular docking against BACE-1 protein revealed that hecogenin, identified from S. cordifolia has a broad spectrum of pharmacological applications and a binding affinity score of -11.3 kcal/Mol. The Hecogenin-BACE-1 protein complex was found to be stable after 30 ns of MD simulation, resulting in its substantial stability. Further studies focusing on the in vivo neuroprotective activity of hecogenin against the disease will pave the way for efficient drug discovery from natural sources in a precise manner.

In Silico Development of Novel Benzofuran-1,3,4-Oxadiazoles as Lead Inhibitors of M. tuberculosis Polyketide Synthase 13.

Benzofuran and 1,3,4-oxadiazole are privileged and versatile heterocyclic pharmacophores which display a broad spectrum of biological and pharmacological therapeutic potential against a wide variety of diseases. This article reports in silico CADD (computer-aided drug design) and molecular hybridization approaches for the evaluation of the chemotherapeutic efficacy of 16 S-linked N-phenyl acetamide moiety containing benzofuran-1,3,4-oxadiazole scaffolds BF1-BF16. This virtual screening was carried out to discover and assess the chemotherapeutic efficacy of BF1-BF16 structural motifs as Mycobacterium tuberculosis polyketide synthase 13 (Mtb Pks13) enzyme inhibitors. The CADD study results revealed that the benzofuran clubbed oxadiazole derivatives BF3, BF4, and BF8 showed excellent and remarkably significant binding energies against the Mtb Pks13 enzyme comparable with the standard benzofuran-based TAM-16 inhibitor. The best binding affinity scores were displayed by 1,3,4-oxadiazoles-based benzofuran scaffolds BF3 (-14.23 kcal/mol), BF4 (-14.82 kcal/mol), and BF8 (-14.11 kcal/mol), in comparison to the binding affinity score of the standard reference TAM-16 drug (-14.61 kcal/mol). 2,5-Dimethoxy moiety-based bromobenzofuran-oxadiazole derivative BF4 demonstrated the highest binding affinity score amongst the screened compounds, and was higher than the reference Pks13 inhibitor TAM-16 drug. The bindings of these three leads BF3, BF4, and BF8 were further confirmed by the MM-PBSA investigations in which they also exhibited strong bindings with the Pks13 of Mtb. Moreover, the stability analysis of these benzofuran-1,3,4-oxadiazoles in the active sites of the Pks13 enzyme was achieved through molecular dynamic (MD) simulations at 250 ns virtual simulation time, which indicated that these three in silico predicted bio-potent benzofuran tethered oxadiazole molecules BF3, BF4, and BF8 demonstrated stability with the active site of the Pks13 enzyme.

Energy-based generative models for target-specific drug discovery.

Drug targets are the main focus of drug discovery due to their key role in disease pathogenesis. Computational approaches are widely applied to drug development because of the increasing availability of biological molecular datasets. Popular generative approaches can create new drug molecules by learning the given molecule distributions. However, these approaches are mostly not for target-specific drug discovery. We developed an energy-based probabilistic model for computational target-specific drug discovery. Results show that our proposed TagMol can generate molecules with similar binding affinity scores as real molecules. GAT-based models showed faster and better learning relative to Graph Convolutional Network baseline models.

Identification of novel inhibitors for trigger factor (TF) of M. tb: an in silico investigation

Trigger factor, as a chaperone protein, is required for survival of Mycobacterium tuberculosis (M.tb) in a stressed environment. This protein interacts with various partners in both the pre- and the post-translation processes, yet the crystal structures of the M.tb trigger factor remain unresolved. In this study, we developed a homology model of M.tb trigger factor to facilitate the discovery and design of inhibitors. To validate the model, we employed several methodologies, including Ramachandran plot and molecular dynamics simulations. The simulations showed a stable trajectory, indicating the accuracy of the model. The active site of M.tb Trigger Factor was identified based on site scores, and virtual screening of over 70,000 compounds led to the identification of two potential hits: HTS02984 (ethyl 2-(3-(4-fluorophenyl)ureido)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate) and S06856 ((E)-N-(4-((2-(4-(tert-butyl)benzoyl)hydrazono)methyl)phenyl) acetamide). These compounds showed strong binding affinity and energy scores, and their chemical descriptors were evaluated. Our study provides a reliable computational model for M.tb Trigger Factor and identifies two potential inhibitors for this crucial protein, which could aid in the development of novel therapies against tuberculosis. Communicated by Ramaswamy H. Sarma