Synthesis, optical properties, DNA, ß-cyclodextrin interactions, and antioxidant evaluation of novel isoxazolidine derivative (ISoXD2): A multispectral and computational analysis.

ISoXD2 are well explored among versatile and outstanding class of pharmacophores for the preparation and discovery of drugs. Herein, the electronic absorption and emission spectra of ISoXD2 were investigated in three different solvents. The observed transition was attributed to π-π* with charge transfer character. Changes in the excited state and shift of the absorption and emission peaks to longer wavelengths are observed as a result of increasing solvent polarity, due to the interactions between the ISoXD2 molecule and the solvent molecules surrounding it. Changing the solvent confirms its solvatochromic effect. UV-vis and fluorescence analysis revealed that ISoXD2 binds to deoxyribonucleic acid (DNA) by intercalation mode, with a stoichiometric ratio of 1:1.5. Moreover, the fluorescence intensity of DNA bound to ethidium bromide (EB) in the presence of ISoXD2 was investigated. From this analysis, the Stern-Volmer quenching constant (Ksv), quenching rate constant (kq), binding constant (Kb) and binding sites number (n) were found to be 5.654 × 103 M-1, 2.827 × 1011 M-1 s-1, 3.81 × 104 M-1 and 1.225, respectively. The interaction between ISoXD2 and ß-CD was investigated through absorption spectra analysis. Kb for this interaction was determined to be 4.9 × 104 M-1. The free radical-scavenging ability of the prepared ISoXD2, examined by DPPH and ABTS assays have shown a good antioxidant activity. Furthermore, modeling study was conducted to explore their plausible binding mechanism with ISoXD2 and to support the experimental results.

Current strategies to address data scarcity in artificial intelligence-based drug discovery: A comprehensive review.

Artificial intelligence (AI) has played a vital role in computer-aided drug design (CADD). This development has been further accelerated with the increasing use of machine learning (ML), mainly deep learning (DL), and computing hardware and software advancements. As a result, initial doubts about the application of AI in drug discovery have been dispelled, leading to significant benefits in medicinal chemistry. At the same time, it is crucial to recognize that AI is still in its infancy and faces a few limitations that need to be addressed to harness its full potential in drug discovery. Some notable limitations are insufficient, unlabeled, and non-uniform data, the resemblance of some AI-generated molecules with existing molecules, unavailability of inadequate benchmarks, intellectual property rights (IPRs) related hurdles in data sharing, poor understanding of biology, focus on proxy data and ligands, lack of holistic methods to represent input (molecular structures) to prevent pre-processing of input molecules (feature engineering), etc. The major component in AI infrastructure is input data, as most of the successes of AI-driven efforts to improve drug discovery depend on the quality and quantity of data, used to train and test AI algorithms, besides a few other factors. Additionally, data-gulping DL approaches, without sufficient data, may collapse to live up to their promise. Current literature suggests a few methods, to certain extent, effectively handle low data for better output from the AI models in the context of drug discovery. These are transferring learning (TL), active learning (AL), single or one-shot learning (OSL), multi-task learning (MTL), data augmentation (DA), data synthesis (DS), etc. One different method, which enables sharing of proprietary data on a common platform (without compromising data privacy) to train ML model, is federated learning (FL). In this review, we compare and discuss these methods, their recent applications, and limitations while modeling small molecule data to get the improved output of AI methods in drug discovery. Article also sums up some other novel methods to handle inadequate data.

Exploration of novel cationic amino acid-enriched short peptides: design, SPPS, biological evaluation and in silico study.

Antimicrobial resistance (AMR) represents a critical challenge worldwide, necessitating the pursuit of novel approaches to counteract bacterial and fungal pathogens. In this context, we explored the potential of cationic amino acid-enriched short peptides, synthesized via solid-phase methods, as innovative antimicrobial candidates. Our comprehensive evaluation assessed the antibacterial and antifungal efficacy of these peptides against a panel of significant pathogens, including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pyogenes, Candida albicans, and Aspergillus niger. Utilizing molecular docking techniques, we delved into the molecular interactions underpinning the peptides' action against these microorganisms. The results revealed a spectrum of inhibitory activities, with certain peptide sequences displaying pronounced effectiveness across various pathogens. These findings underscore the peptides' potential as promising antimicrobial agents, with molecular docking offering valuable insights into their mechanisms of action. This study enriches antimicrobial peptide (AMP) research by identifying promising candidates for further refinement and development toward therapeutic application, highlighting their significance in addressing the urgent issue of AMR.

Design and Synthesis of the Linezolid Bioisosteres to Resolve the Serotonergic Toxicity Associated with Linezolid.

Serotonergic toxicity due to MAO enzyme inhibition is a significant concern when using linezolid to treat MDR-TB. To address this issue, we designed linezolid bioisosteres with a modified acetamidomethyl side chain at the C-5 position of the oxazolidine ring to balance activity and reduce toxicity. Among these bioisosteres, R7 emerged as a promising candidate, demonstrating greater effectiveness against M. tuberculosis (Mtb) H37Rv cells with an MIC of 2.01 µM compared to linezolid (MIC = 2.31 µM). Bioisostere R7 also exhibited remarkable activity (MIC50) against drug-resistant Mtb clinical isolates, with values of 0.14 µM (INHR, inhA+), 0.53 µM (INHR, katG+), 0.24 µM (RIFR, rpoB+), and 0.92 µM (INHR INHR, MDR). Importantly, it was >6.52 times less toxic as compared to the linezolid toward the MAO-A and >64 times toward the MAO-B enzyme, signifying a substantial improvement in its drug safety profile.

Exploring the structural activity relationship of the Osimertinib: A covalent inhibitor of double mutant EGFRL858R/T790M tyrosine kinase for the treatment of Non-Small Cell Lung Cancer (NSCLC).

The USFDA granted regular approval to Osimertinib (AZD9291) on March 2017, for treating individuals with metastatic Non-Small Cell Lung Cancer having EGFR T790M mutation. Clinically, Osimertinib stands at the forefront for the treatment of patients with Non-Small Cell Lung Cancer. Osimertinib forms a covalent bond with the Cys797 residue and predominantly spares binding to WT-EGFR, thereby reducing toxicity and enabling the administration of doses that effectively inhibit T790M. However, a high percentage of patients treated with Osimertinib (AZD9291) developed a tertiary cysteine797 to serine797 (C797S) mutation in the EGFR kinase domain, rendering resistance to it. This comprehensive review sheds light on the chemistry, computational aspects, structural features, and expansive spectrum of biological activities of Osimertinib and its analogues. The in-depth exploration of these facets serves as a valuable resource for medicinal chemists, empowering them to design better Osimertinib analogues. This exhaustive study not only provides insights into improving potency but also emphasizes considerations for mutant selectivity and optimizing pharmacokinetic properties. This review acts as a guiding beacon for the strategic design and development of next-generation Osimertinib analogues.

New tetrahydroisoquinoline-4-carbonitrile derivatives as potent agents against cyclin-dependent kinases, crystal structures, and computational studies.

The synthesis of two new hexahydroisoquinoline-4-carbonitrile derivatives (3a and 3b) is reported along with spectroscopic data and their crystal structures. In compound 3a, the intramolecular O-H···O hydrogen bond constraints the acetyl and hydroxyl groups to be syn. In the crystal, inversion dimers are generated by C-H···O hydrogen bonds and are connected into layers parallel to (10-1) by additional C-H···O hydrogen bonds. The layers are stacked with Cl···S contacts 0.17 Å less than the sum of the respective van der Waals radii. The conformation of the compound 3b is partially determined by the intramolecular O-H···O hydrogen bond. A puckering analysis of the tetrahydroisoquinoline unit was performed. In the crystal, O-H···O and C-H···O hydrogen bonds together with C-H···π(ring) interactions form layers parallel to (01-1) which pack with normal van der Waals interactions. To understand the binding efficiency and stability of the title molecules, molecular docking, and 100 ns dynamic simulation analyses were performed with CDK5A1. To rationalize their structure-activity relationship(s), a DFT study at the B3LYP/6-311++G** theoretical level was also done. The 3D Hirshfled surfaces were also taken to investigate the crystal packings of both compounds. In addition, their ADMET properties were explored.Communicated by Ramaswamy H. Sarma.

Synthesis, DFT Calculations, In Silico Studies, and Antimicrobial Evaluation of Benzimidazole-Thiadiazole Derivatives.

In this study, a series of new benzimidazole-thiadiazole hybrids were synthesized, and the synthesized compounds were screened for their antimicrobial activities against eight species of pathogenic bacteria and three fungal species. Azithromycin, voriconazole, and fluconazole were used as reference drugs in the mtt assay. Among them, compounds 5f and 5h showed potent antifungal activity against C. albicans with a MIC of 3.90 µg/mL. Further, the results of the antimicrobial assay for compounds 5a, 5b, 5f, and 5h proved to be potent against E. faecalis (ATCC 2942) on the basis of an acceptable MIC value of 3.90 µg/mL. The cytotoxic effects of compounds that are effective as a result of their antimicrobial activity on healthy mouse fibroblast cells (L929) were evaluated. According to HOMO-LUMO analysis, compound 5h (with the lower ΔE = 3.417 eV) is chemically more reactive than the other molecules, which is compatible with the highest antibacterial and antifungal activity results. A molecular docking study was performed to understand their binding modes within the sterol 14-α demethylase active site and to interpret their promising fungal inhibitory activities. Molecular dynamics (MD) simulations of the most potent compounds 5f and 5h were found to be quite stable in the active site of the 14-α demethylase (5TZ1) protein.

Synthesis, Molecular Docking, Molecular Dynamic Simulation Studies, and Antitubercular Activity Evaluation of Substituted Benzimidazole Derivatives.

Tuberculosis, also known as TB, is a widespread bacterial infection that remains a significant global health issue. This study focuses on conducting a thorough investigation into the synthesis, evaluation of anti-Tb activity, molecular docking, and molecular dynamic simulation of substituted benzimidazole derivatives. A series of twelve substituted benzimidazole derivatives (1-12) were successfully synthesized, employing a scaffold consisting of electron-withdrawing and electron-donating groups. The newly synthesized compounds were defined by their FTIR, 1H NMR, and mass spectra. The microplate Alamar blue assay (MABA) was used to evaluate the antimycobacterial activity of the synthesized compound against Mycobacterium tuberculosis (Mtb). Compounds 7 (MIC = 0.8 g/mL) and 8 (MIC = 0.8 g/mL) demonstrated exceptional potential to inhibit M. tuberculosis compared to the standard drug (isoniazid). In addition, the synthesized compounds were docked with the Mtb KasA protein (PDB ID: 6P9K), and the results of molecular docking and molecular dynamic simulation confirmed the experimental results, as compounds 7 and 8 exhibited the highest binding energy of -7.36 and -7.17 kcal/mol, respectively. The simulation results such as the RMSD value, RMSF value, radius of gyration, and hydrogen bond analysis illustrated the optimum potential of compounds 7 and 8 to inhibit the M. tuberculosis strain. Hydrogen bond analysis suggested that compound 7 has greater stability and affinity towards the KasA protein compared to compound 8. Moreover, both compounds (7 and 8) were safe for acute inhalation and cutaneous sensitization. These two compounds have the potential to be potent M. tuberculosis inhibitors.

Computational and in vitro screening validates the repositioning potential of Coxibs as anti-fibrotic agents.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with a survival rate of <5 years. The TGF-ß plays a significant role in the progression and severity of IPF. The TGF-ß receptor type1 TGFBR1 antagonists inhibit the process of fibrosis and may have a role in the treatment of IPF. The main objective of the study was to identify promising drug candidates against IPF using In-silico and In-vitro evaluation methods. An in-silico screening was carried out of the marketed Coxibs to find their TGFBR1 inhibitory potential considering their structural resemblance with the JZO-a co-crystalized ligand of the crystal structure of the TGFBR1. The virtual screening yielded rofecoxib as a TGFBR1 ligand with a significant docking score. To further validate the outcome of molecular docking studies, MD simulation of 200 ns was carried out followed by the determination of conformational stability, binding free energy calculation using MMPBSA/MMGBSA, and Free Energy Landscape (FEL). The therapeutic efficacy of rofecoxib was compared with that of nintedanib (a therapeutic agent used in the treatment of IPF) at equimolar concentrations (5 µM). The model of TGF-ß1 (1 ng/ml)-induced EMT of A549 was used to determine the effect of rofecoxib on the EMT markers like cellular morphology, cytokine expressions, fibrosis associated protein, E-cadherin, and α-smooth muscle actin. In vitro results indicated that rofecoxib significantly suppresses the TGF-ß1-induced EMT of A549 cells and validates the possible preventive/protective role of rofecoxib in pulmonary fibrosis. In conclusion, rofecoxib may be considered for repositioning as an anti-fibrotic agent.Communicated by Ramaswamy H. Sarma.

Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches.

In the development of novel antidiabetic agents, a novel series of isoxazolidine-isatin hybrids were designed, synthesized, and evaluated as dual α-amylase and α-glucosidase inhibitors. The precise structures of the synthesized scaffolds were characterized using different spectroscopic techniques and elemental analysis. The obtained results were compared to those of the reference drug, acarbose (IC50 = 296.6 ± 0.825 µM for α-amylase & IC50 = 780.4 ± 0.346 µM for α-glucosidase). Among the title compounds, 5d exhibited impressive α-amylase and α-glucosidase inhibitory activity with IC50 values of 30.39 ± 1.52 µM and 65.1 ± 3.11 µM, respectively, followed by 5h (IC50 = 46.65 ± 2.3 µM; IC50 = 85.16 ± 4.25 µM) and 5f (IC50 = 55.71 ± 2.78 µM; IC50 = 106.77 ± 5.31 µM). Mechanistic studies revealed that the most potent derivative 5d bearing the chloro substituent attached to the oxoindolin-3-ylidene core, and acarbose, are a competitive inhibitors of α-amylase and α-glucosidase, respectively. Structure activity relationship (SAR) was examined to guide further structural optimization of the most appropriate substituent(s). Moreover, drug-likeness qualities and ADMET prediction of the most active analogue, 5d was also performed. Subsequently, 5d was subjected to molecular docking and dynamic simulation during the progression of 120 ns analysis to check the essential ligand-receptor patterns, and to estimate its stability. In silico studies were found in good agreement with the in vitro enzymatic inhibitions results. In conclusion, we demonstrated that most potent compound 5d could be exploited as dual potential inhibitor of α-amylase and α-glucosidase for possible management of diabetes.

Isolation, characterization, and multimodal evaluation of novel glycolipid biosurfactant derived from Bacillus species: A promising Staphylococcus aureus tyrosyl-tRNA synthetase inhibitor through molecular docking and MD simulations.

Glycolipid-based biosurfactants (BSs), known for their intriguing and diverse properties, represent a largely uncharted territory in the realm of potential biomedical applications. This field holds great promise yet remains largely unexplored. This investigation provides new insights into the isolation, characterization, and comprehensive biomedical assessment of a novel glycolipid biosurfactant derived from Bacillus species, meeting the growing demand for understanding its multifaceted impact on various biomedical issues. Within this framework, two glycolipids, BG2A and BG2B, emerged as the most proficient strains in biosurfactant (BS) production. The biosurfactants (BSs) ascertained as glycolipids via thin layer chromatography (TLC) exhibited antimicrobial activity against S. aureus and E. coli. Both isolates exhibited anticancer effects against cervical carcinoma cells and demonstrated significant anti-biofilm activity against V. cholerae. Moreover, molecular docking and molecular dynamics (MD) simulations were employed to explore their antimicrobial resistance properties against Tyrosyl-tRNA synthetase (TyrRS) of Staphylococcus aureus, a well-annotated molecular target. Characterization and interpretation using Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (1H and 13C NMR) confirmed that the BSs produced by each strain were glycolipids. These findings suggest that the isolated BSs can serve as effective agents with antibiofilm, antimicrobial, antioxidant, and anticancer properties, in addition to their considerable antibacterial resistance attributes.

Generative artificial intelligence in drug discovery: basic framework, recent advances, challenges, and opportunities.

There are two main ways to discover or design small drug molecules. The first involves fine-tuning existing molecules or commercially successful drugs through quantitative structure-activity relationships and virtual screening. The second approach involves generating new molecules through de novo drug design or inverse quantitative structure-activity relationship. Both methods aim to get a drug molecule with the best pharmacokinetic and pharmacodynamic profiles. However, bringing a new drug to market is an expensive and time-consuming endeavor, with the average cost being estimated at around $2.5 billion. One of the biggest challenges is screening the vast number of potential drug candidates to find one that is both safe and effective. The development of artificial intelligence in recent years has been phenomenal, ushering in a revolution in many fields. The field of pharmaceutical sciences has also significantly benefited from multiple applications of artificial intelligence, especially drug discovery projects. Artificial intelligence models are finding use in molecular property prediction, molecule generation, virtual screening, synthesis planning, repurposing, among others. Lately, generative artificial intelligence has gained popularity across domains for its ability to generate entirely new data, such as images, sentences, audios, videos, novel chemical molecules, etc. Generative artificial intelligence has also delivered promising results in drug discovery and development. This review article delves into the fundamentals and framework of various generative artificial intelligence models in the context of drug discovery via de novo drug design approach. Various basic and advanced models have been discussed, along with their recent applications. The review also explores recent examples and advances in the generative artificial intelligence approach, as well as the challenges and ongoing efforts to fully harness the potential of generative artificial intelligence in generating novel drug molecules in a faster and more affordable manner. Some clinical-level assets generated form generative artificial intelligence have also been discussed in this review to show the ever-increasing application of artificial intelligence in drug discovery through commercial partnerships.

Synthesis, biological evaluation, and In silico molecular docking of N-(4-(4-substitutedphenyl)-6-(substituted aryl) pyrimidin-2-yl)-2-(2-isonicotinoyl hydrazinyl) acetamide.

Isonicotinohydrazide is the first-line medication in the prevention and treatment of tuberculosis. Antitubercular, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial activity, anticancer, antineoplastic activity, and anti-HIV activity are all demonstrated by drugs with a pyrimidine ring. The current study focuses on the synthesis of N-(4-(substituted-phenyl)-6-(substituted-aryl) pyrimidin-2-yl)-2-(2-isonicotinoylhydrazinyl) acetamide from isonicotinohydrazide. Newly synthesized compounds were characterized by spectral studies (IR, 1 H-NMR, 13 C-NMR, and mass spectroscopy). They were screened for their antituberculosis, antimalarial, and antiprotozoal activities and compared with standard drugs. Molecular docking of isonicotinohydrazide-bearing pyrimidine motifs was also done for some of the active compounds.

Design, synthesis, biological evaluation, and in silico studies of quinoxaline derivatives as potent p38α MAPK inhibitors.

A new series of quinoxaline derivatives possessing the hydrazone moiety were designed, synthesized, and screened for in-vitro anti-inflammatory activity by the bovine serum albumin (BSA) denaturation technique, and for antioxidant activity, by the (2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The synthesized compounds were also tested for p38α mitogen-activated protein (MAP) kinase inhibition. The in-vivo anti-inflammatory activity was assessed by the carrageenan-induced rat paw edema inhibition method. All the compounds (4a-n) exhibited moderate to high in-vitro anti-inflammatory activity. Compound 4a displayed the highest inhibitory activity in the BSA assay (83.42%) in comparison to the standard drug diclofenac sodium (82.90%), while 4d exhibited comparable activity (81.87%). The DPPH assay revealed that compounds 4a and 4d have free radical scavenging potential (74.70% and 74.34%, respectively) comparable to the standard butylated hydroxyanisole (74.09%). Furthermore, the p38α MAP kinase inhibition assay demonstrated that compound 4a is highly selective against p38α MAP kinase (IC50 = 0.042) in comparison to the standard SB203580 (IC50 = 0.044). The five most active compounds (4a-4d and 4f) with good in-vitro profiles were selected for in-vivo anti-inflammatory studies. Compounds 4a and 4d were found to display the highest activity (83.61% and 82.92% inhibition, respectively) in comparison to the standard drug diclofenac sodium (82.65% inhibition). These compounds (4a and 4d) also exhibited better ulcerogenic and lipid peroxidation profiles than diclofenac sodium. The molecular docking and molecular dynamics simulation studies were also performed and found to be in agreement with the p38α MAP kinase inhibitory activity.

Benzimidazole and piperidine containing novel 1,2,3-triazole hybrids as anti-infective agents: Design, synthesis, in silico and in vitro antimicrobial efficacy.

Cu alkyne-azide cycloaddition was used to easily synthesize a library of novel heterocycles containing benzimidazole and piperidine based 1,2,3-triazole(7a-7l) derivatives. The synthesized analogs were characterized by various spectroscopic techniques like FTIR, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass spectrometry. All these novel bioactive compounds (7a-7l) were evaluated for in vitro antibacterial and antifungal efficacy. Compound 7k exhibited appreciable potent activity against Escherichia coli strain. Compounds 7a, 7b, 7f, and 7i showed excellent potent activity against all bacterial strains. Compound 7b, 7c, 7d, and 7g derivatives showed excellent effects when tested in vitro for antifungal activity against various fungal strains. Additionally, a molecular docking investigation revealed that compound 7k has the ability to bind to the active site of the E. coli DNA gyrase subunit protein and form hydrogen bonds with significant amino acid residues Asp73 and Asp49 in the active sites. In a 100 ns molecular dynamics simulation, the E. coli DNA gyrase protein's steady capacity to bind compound 7k was shown by the low measured root mean square deviation, which was an indication of the complex's conformational stability.

Synthesis, biological evaluation and molecular modeling studies of modulated benzyloxychalcones as potential acetylcholinesterase inhibitors.

Acetylcholinesterase inhibitors (AChEIs) have become a significant target in the search for an efficient treatment of Alzheimer's disease. Chalcone-based compounds display a strong potency to hinder AChE. So, this study focused on the synthesis of a series of new chalcone derivatives with anti-cholinesterase potential and their structures were characterized based on spectroscopic methods including IR, 1H NMR, 13C NMR and HRMS. Chalcone derivatives were screened against AChE. Most of them exhibited potent inhibitory activity against AChE. Compound 11i showed the most potent activity toward acetylcholinesterase compared to the positive compound, Galantamine. Docking studies into the active site of the acetylcholinesterase enzyme ravealed the significant docking score of the synthesized compounds with docking score of -7.959 to -9.277 kcal/mol when compared to the co-crystallized ligand, Donepezil (-10.567 kcal/mol). The interaction's stability was further assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound 11i in the cavity of the acetylcholinesterase enzyme.Communicated by Ramaswamy H. Sarma.

Investigation of new 1,2,3-triazolyl-quinolinyl-propan-2-ol derivatives as potential antimicrobial agents: in vitro and in silico approach.

A new series of 1-((1-(4-substituted benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2-substituted quinolin-4-yl)propan-2-ol (9a-x) have been synthesized. The newly synthesized 1,2,3-triazolyl-quinolinyl-propan-2-ol (9a-x) derivatives were screened for in vitro antimicrobial activity against M. tuberculosis H37Rv, E. coli, P. mirabilis, B. subtilis, and S. albus. Most of the compounds showed good to moderate antibacterial activity and all derivatives have shown excellent to good antitubercular activity with MIC 0.8-12.5 µg/mL. To know the plausible mode of action for antibacterial activity the docking study against DNA gyrase from M. tuberculosis and S. aureus was investigated. The compounds have shown significant docking scores in the range of -9.532 to -7.087 and -9.543 to -6.621 Kcal/mol with the DNA gyrase enzyme of S. aureus (PDB ID: 2XCT) and M. tuberculosis (PDB ID: 5BS8), respectively. Against the S. aureus and M. tuberculosis H37Rv strains, the compound 9 l showed good activity with MIC values of 62.5 and 3.33 µM. It also showed significant docking scores in both targets with -8.291 and -8.885 Kcal/mol, respectively. Molecular dynamics was studied to investigate the structural and dynamics transitions at the atomistic level in S. aureus DNA gyrase (2XCT) and M. tuberculosis DNA gyrase (5BS8). The results revealed that the residues in the active binding pockets of the S. aureus and M. tuberculosis DNA gyrase proteins that interacted with compound 9 l remained relatively consistent throughout the MD simulations and thus, reflected the conformation stability of the respective complexes. Thus, the significant antimicrobial activity of derivatives 9a-x recommended that these compounds could assist in the development of lead compounds to treat for bacterial infections.Communicated by Ramaswamy H. Sarma.

Carbazole derivatives as promising competitive and allosteric inhibitors of human serotonin transporter: computational pharmacology.

The human serotonin transporters (hSERTs) are neurotransmitter sodium symporters of the aminergic G protein-coupled receptors, regulating the synaptic serotonin and neuropharmacological processes related to neuropsychiatric disorders, notably, depression. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and (S)-citalopram are competitive inhibitors of hSERTs and are commonly the first-line medications for major depressive disorder (MDD). However, treatment-resistance and unpleasant aftereffects constitute their clinical drawbacks. Interestingly, vilazodone emerged with polypharmacological (competitive and allosteric) inhibitions on hSERTs, amenable to improved efficacy. However, its application usually warrants adjuvant/combination therapy, another subject of critical adverse events. Thus, the discovery of alternatives with polypharmacological potentials (one-drug-multiple-target) and improved safety remains essential. In this study, carbazole analogues from chemical libraries were explored using docking and molecular dynamics (MD) simulation. Selectively, two IBScreen ligands, STOCK3S-30866 and STOCK1N-37454 predictively bound to the active pockets and expanded boundaries (extracellular vestibules) of the hSERTs more potently than vilazodone and (S)-citalopram. For instance, the two ligands showed docking scores of -9.52 and -9.59 kcal/mol and MM-GBSA scores of -92.96 and -65.66 kcal/mol respectively compared to vilazodone's respective scores of -7.828 and -59.27 against the central active site of the hSERT (PDB 7LWD). Similarly, the two ligands also docked to the allosteric pocket (PDB 5I73) with scores of -8.15 and -8.40 kcal/mol and MM-GBSA of -96.14 and -68.46 kcal/mol whereas (S)-citalopram has -6.90 and -69.39 kcal/mol respectively. The ligands also conferred conformational stability on the receptors during 100 ns MD simulations and displayed interesting ADMET profiles, representing promising hSERT modulators for MDD upon experimental validation.Communicated by Ramaswamy H. Sarma.

In silico analysis to identify potential antitubercular molecules in Morus alba through virtual screening and molecular dynamics simulations.

A major obstacle in the treatment of tuberculosis (TB) is to combat the emerging resistant strains of its causing agent i.e. Mycobacterium tuberculosis (MTb). The emergence of multidrug-resistant and extensively drug-resistant -TB strains raise a requirement of new potential anti-tubercular compounds. In this direction, different plant parts of Morus alba were tested against MTb and found to be active with a minimum inhibitory concentration ranging between 125 µg/ml to 31.5 µg/ml. Further to identify the phytochompounds having anti-mycobacterium activity, phytocompounds of the plant were docked against the five MTb proteins (PDB ID: 3HEM, 4OTK, 2QO0, 2AQ1 and 6MNA). Among twenty-two tested phytocompounds, four phytocompounds with effective binding energy (kcal/mol): Petunidin-3-rutinoside (3HEM: -8.2, 4OTK: -6.9, 2QO0: -9.0, 2AQ1: -8.3 and 6MNA:-7.8), Quercetin-3'-glucoside (3HEM:-6.7, 4OTK:-7.6, 2QO0:-7.6, 2AQ1:7.6 and 6MNA:-6.4), Rutin (3HEM:-7.8, 4OTK:-7.5, 2QO0:-9.1, 2AQ1:9.3 and 6MNA:-6.9) and Isoquercitrin (3HEM:-7.3, 4OTK:-6.6, 2QO0:-7.7, 2AQ1:8.3 and 6MNA:-6.6) shows promising activity against all the five target proteins. Further molecular dynamics studies of Petunidin-3-rutinoside with three target proteins 3HEM, 2AQ1 and 2QO0 resulted with low values of average RMSD (3.723 Å, 3.261 Å, and 2.497 Å, respectively) show that the complexes have better conformational stability. The wet lab validation of the current study will pave the new dimensions for the cure of TB patients.Communicated by Ramaswamy H. Sarma.

GC-MS screening of the phytochemical composition of Ziziphus honey: ADME properties and in vitro/in silico study of its antimicrobial activity.

A revival interest has been given to natural products as sources of phytocompounds to be used as alternative treatment against infectious diseases. In this context, we aimed to investigate the antimicrobial potential of Ziziphus honey (ZH) against twelve clinical bacterial strains and several yeasts and molds using in vitro and computational approaches. The well-diffusion assay revealed that ZH was able to induce growth inhibition of most Gram-positive and Gram-negative bacteria. The high mean growth inhibition zone (mGIZ) was recorded in E. coli (Clinical strain, 217), S. aureus followed by E. coli ATCC 10536 (mGIZ values: 41.00 ± 1 mm, 40.67 ± 0.57 mm, and 34.67 ± 0.57 mm, respectively). The minimal bactericidal concentrations (MBCs) and minimal fungicidal concentration values (MFCs) from approximately 266.33 mg/mL to over 532.65 mg/mL. Molecular docking results revealed that the identified compounds maltose, 2-furoic acid, isopropyl ester, 2,4-imidazolidinedione, 5-(2-methylpropyl)-(S)- and 3,4,5-trihydroxytoluene, S-Methyl-L-Cysteine, 2-Furancarboxylic acid, L-Valine-N-ethoxycarbonyl, Hexanoic acid, 3,5,5-trimethyl-, Methyl-beta-D-thiogalactoside, gamma-Sitosterol, d-Mannose, 4-O-Methylmannose, 2,4-Imidazolidinedione, 5-(2-methylpropyl)- (S) were found to have good affinity for targeted receptor, respectively. Through a 100-ns dynamic simulation research, binding interactions and stability between promising phytochemicals and the active residues of the studied enzymes were confirmed. The ADMET profiling of all identified compounds revealed that most of them could be qualified as biologically active with good absorption and permeation. Overall, the results highlighted the efficiency of ZH against the tested clinical pathogenic strains. The antimicrobial potential and the potency displayed by the identified compounds could imply their further pharmacological applications.Communicated by Ramaswamy H. Sarma.