Antiviral multitarget inhibitory capacity of certain structural candidates against antiviral targets, M-pro, PLpro, and RBD-ACE2 interface were assessed in a modular approach. Among the structures analyzed, the compound tiliroside, present in Zygophyllum coccineum, emerged as the potent multitarget inhibitor in the molecular docking studies. Molecular dynamics simulations, performed for 100 ns in triplicate, confirmed the binding stability of the compound to M-pro, PLpro, and RBD-ACE2 interface, together with MM-GBSA binding affinities of similar to -93.55, -68.55, and -62.39 kcal/mol, respectively. The protein backbone RMSDs for these complexes remained within the range of similar to 1.7 to 2.8 & Aring;, indicating stable complexes. The root mean square fluctuation (RMSF) analysis, secondary structure monitoring, principal component analysis, clustering, and Gibbs free energy landscape assessments supported the stability of these complexes. Additionally, residue-specific interaction analysis and binding energy decomposition provided insights into the key elements driving these bindings. The results underscored the potential of the tiliroside as a multitarget inhibitor of viral proteins.

Alzheimer's disease (AD), characterized by cognitive decline, behavioral changes, and amnesia, ultimately leads to dementia in older people. Despite decades of study, there is still no effective way to prevent, retard, or reduce the symptoms of AD. In this paper, we report indole-based heterocyclic conjugates as cholinesterase inhibitors. Compounds 14c (IC50s AChE = 0.30 mu M; BuChE = 10.16 mu M) and 14h (IC50s AChE = 0.58 mu M; BuChE = 15.13 mu M) display efficacy against both AChE and BuChE. These derivatives did not exhibit toxicity against the HEK293 and SH-SY5Y cell lines. Docking analysis demonstrated better binding affinity of these compounds (docking score, 14c = -9.06 kcal/mol; 14h = -9.03 kcal/mol) with recombinant human acetylcholinesterase (PDB ID:4EY7) as compared to the reference drug donepezil (-8.52 kcal/mol). Molecular dynamics analysis demonstrated better MMGBSA binding free energy of these compounds (14c = -33.10 kcal/mol; 14h = -36.64 kcal/mol) with recombinant human acetylcholinesterase as compared to the reference drug donepezil (-32.20 kcal/mol). These compounds bind in the active site of acetylcholinesterase and maintain stability similar to donepezil during a 200 ns MD simulation. Moreover, these compounds exhibit recognizable ADME characteristics.

This mini-review reports on effects that tautomerism has on predicted and clinically observed small-molecule properties important for drug design and drug behaviour in the patient. We present examples of both pharmacokinetics and pharmacodynamics effects. The importance of tautomerism on drugs’ formulation and possible interconversion of stereoisomers is also discussed.

Selective inhibition of histone deacetylase 8 (HDAC8) has emerged as a promising approach for treating various diseases, including cancer. However, finding key structural features for HDAC8 inhibition and developing effective and selective HDAC8 inhibitors (HDAC8is) pose significant challenges. In the past few years, the development of various scaffolds for inhibiting HDAC8 has significantly risen and the quest continues. In such cases, N-heterocyclic derivatives (such as thiazine, indole/pyrrole, pyrazole, triazole, indole, etc.) can play a crucial role in the discovery of novel selective HDAC8 inhibitors. In this current work, Bayesian and SARpy QSAR models were established on a structurally diverse set of 188 selective HDAC8 inhibitors after an extensive literature search. QSAR modelling suggests N-heterocyclic rings as important structural fingerprints for selective as well as promising HDAC8 inhibition. Further, molecular docking and molecular dynamics (MD) simulation studies were carried out on selected compounds (4, 15, 36, 40, and 188) containing N-heterocyclic rings to emphasize the significance of these scaffolds in HDAC8 potency. In addition to this, toxicity studies were carried out using density functional theory (DFT) to determine the toxicity profile of investigated compounds which indicated that the compounds are non-toxic. The outcomes of this research will aid in the exploration of certain key directions for the selective HDAC8 inhibitor design that could speed up the search for anticancer drugs.

An efficient and practical method for the N-alkynylation of 7-azaindoles has been established by using CuI/DMAP catalytic system at room temperature and in open air. This simple protocol has been successfully employed in the synthesis of a wide range of N-alkynylated 7-azaindoles with good yields. Also, this approach is well-suited for large-scale N-alkynylation reactions. The designed N-alkynylated 7-azaindoles were further subjected to Cu-/Ir-catalyzed alkyne-azide cycloaddition (CuAAC/IrAAC) or "click" reaction for the rapid synthesis of 1,4-/1,5 disubstituted 1,2,3-triazole decorated 7-azaindoles. A mechanistic study based on density functional theory (DFT) calculations and ultraviolet-visible (UV) spectroscopic studies revealed that the CuI and DMAP combination formed a [CuII(DMAP)2I2] species, which acts as an active catalyst. The DFT method was used to assess the energetic viability of an organometallic in the C-N bond formation pathway originating from the [CuII(DMAP)2I2] complex. We expect that the newly designed Cu/DMAP/alkyne system will offer valuable insights into the field of Cu-catalyzed transformations.

We have analyzed forty different databases ranging in size from a few thousand to nearly 100 million molecules, comprising a total of over 200 million structures, for their tautomeric conflicts. A tautomeric conflict is defined as an occurrence of two or more structures within a data set identified by the tautomeric rules applied as being tautomers of each other. We tested a total of 119 detailed tautomeric transform rules expressed as SMIRKS, out of which 79 yielded at least one conflict. The databases analyzed spanned a wide variety of types including large aggregating databases, drug collections, and experimentally based structure collections. Almost all databases analyzed showed intra-database tautomeric conflicts. The conflict rates as percentage of the database were typically in the few tenths of a percent range, which for the largest databases amounts to more than 100,000 cases per database.

Ethnopharmacological relevanceNonalcoholic fatty liver disease (NAFLD) is the most common severe liver disease globally, progressing further into nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Vasaguduchyadi Kwatha (VK) is an Ayurvedic formulation traditionally used to treat liver diseases and other metabolic complications. This study is an ethnopharmacological approach to unravel this indigenous remedy.Aim of the studyWe aimed to discover the probable mechanism of action of VK against NASH in this study, using network pharmacology, molecular docking, in vitro study, and preclinical investigation.Methods and resultsAmong the 55 components identified, 10 were confirmed based on mass, elution charecteristics, MS/MS analysis data, and fragmentation rules. Computational study indicated 92 targets involved in the central pathways of NASH, out of which only 15 targets and 9 VK constituents have significant docking scores. In vitro and in vivo analysis results showed that VK significantly reduces weight gain and improves insulin sensitivity, dyslipidemia, steatohepatitis and overall histological features of NASH compared to saroglitazar (SGZR).ConclusionOur detailed study yielded three signalling pathways related to NASH on which VK has maximum effect, bringing up a probable alternative treatment for NASH.

Histone deacetylases constitute a group of enzymes that participate in several biological processes. Notably, inhibiting HDAC8 has become a therapeutic strategy for various diseases. The current inhibitors for HDAC8 lack selectivity and target multiple HDACs. Consequently, there is a growing recognition of the need for selective HDAC8 inhibitors to enhance the effectiveness of therapeutic interventions. In our current study, we have utilized a multi-faceted approach, including Quantitative Structure-Activity Relationship (QSAR) combined with Quantitative Read-Across Structure-Activity Relationship (q-RASAR) modeling, pharmacophore mapping, molecular docking, and molecular dynamics (MD) simulations. The developed q-RASAR model has a high statistical significance and predictive ability (Q2F1:0.778, Q2F2:0.775). The contributions of important descriptors are discussed in detail to gain insight into the crucial structural features in HDAC8 inhibition. The best pharmacophore hypothesis exhibits a high regression coefficient (0.969) and a low root mean square deviation (0.944), highlighting the importance of correctly orienting hydrogen bond acceptor (HBA), ring aromatic (RA), and zinc-binding group (ZBG) features in designing potent HDAC8 inhibitors. To confirm the results of q-RASAR and pharmacophore mapping, molecular docking analysis of the five potent compounds (44, 54, 82, 102, and 118) was performed to gain further insights into these structural features crucial for interaction with the HDAC8 enzyme. Lastly, MD simulation studies of the most active compound (54, mapped correctly with the pharmacophore hypothesis) and the least active compound (34, mapped poorly with the pharmacophore hypothesis) were carried out to validate the observations of the studies above. This study not only refines our understanding of essential structural features for HDAC8 inhibition but also provides a robust framework for the rational design of novel selective HDAC8 inhibitors which may offer insights to medicinal chemists and researchers engaged in the development of HDAC8-targeted therapeutics.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and remains one of the leading causes of death in older age. While there is no direct cure for AD, very few FDA-approved drugs are available for managing the symptoms by targeting traditional targets. Amyloid-beta (Aß) peptides were identified as a crucial target for AD therapy, in recent times, phenolic compounds have shown the potential to inhibit Amyloid-beta peptide. These phenolic compounds destabilize Aß aggregation, but their inhibition mechanisms are not clearly understood. In this study, we thoroughly explored the molecular binding mechanism of >1000 phenolic compounds with the Aß fibrils via extra precision (XP) and induced fit docking (IFD) methods. Additionally, molecular dynamics (MD) simulations of the top 10 druglike phenolic compounds were performed with a simulation time of 500 nanoseconds (ns). Our results showed that two promising compounds, Rhapontigenin and Okanin, exhibited superior binding free energy and stability compared to the reference apigenin. These compounds effectively disrupted the Asp23-Lys28 salt bridge interactions and hydrogen bond patterns in the Aß fibril. Furthermore, both the identified compounds showed significant van der Waal's interaction with the Aß fibril. Our findings align with the previous studies and provide additional insights into inhibitory mechanisms at the molecular level. Additionally, this study incorporates analysis of non-covalent interactions and DFT studies to further elucidate the mechanisms. Nevertheless, it is crucial to emphasize that these results are based on in silico analyses and necessitate further experimental validation through in vitro and in vivo studies to confirm their efficacy.

Islamic literature has indicated that daily consumption of Ajwa dates heals a variety of chronic diseases and disorders. The current research investigates the neuroprotective effect of methanolic Ajwa seed extract (MASE) on lipopolysaccharide (LPS)-induced cognitive deficits using multiple approaches. For animal studies, MASE (200 and 400 mg/kg, p.o.) was administrated for thirty consecutive days, and four doses of LPS (250 µg/kg, i.p.) were injected to induce neurotoxicity. Memory functions were evaluated using elevated plus-maze and novel object recognition tests. Acetylcholine (ACh) and neuroinflammatory markers (cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and transforming growth factor (TGF)-β1) were estimated in brain tissues. Studies of molecular docking and dynamics were conducted to provide insight into the molecular-level mechanisms. MASE administration resulted in a significant reversal of LPS-induced memory impairment in both maze models. Both doses of MASE elevated the ACh levels in an LPS-treated rat brain. In addition, the extract lowered COX-2 and proinflammatory cytokines (TNF-α and IL-6) while increasing anti-inflammatory cytokines (IL-10 and TGF-β1) in LPS-treated brain tissues. Molecular modeling results revealed that the compound’s ellagic acid, epicatechin, catechin, kaempferol, quercetin, and apigenin have the potential to act as a dual inhibitor of acetylcholinesterase (AChE) and COX-2 and can be responsible for the improvement of both cholinergic and inflammatory conditions, while the cinnamic acid, hesperidin, hesperetin, narengin, and rutin compounds are responsible only for the improvement of cholinergic transmission. The above compounds acted by interacting with the key residues Trp84, Asp72, Gly118, Ser200, Tyr334, and His440, which are responsible for the hydrolysis of ACh in AChE, while the COX-2 is inhibited by interacting with the residues (Val349, Leu352, Tyr355, Tyr385, Ala527, Ser530, and Leu531) of the hydrophobic channel. By promoting cholinergic activity and protecting neuroinflammation in the rat brain, MASE provides neuroprotection against LPS-induced cognitive deficits. Our preliminary findings will help with further drug discovery processes related to neuroinflammation-related neurodegeneration.

Ambroxol hydrochloride is a pharmacological chaperone approved by FDA as an expectorant. Currently, it is used as an antitussive and anti-asthmatic agent. Besides mucolytic properties, ambroxol has antioxidant, anti-inflammatory, and anesthetic properties. Its effects on the central nervous system (CNS) are currently being explored. Ambroxol has been reported to inhibit microglial activation and decreases proinflammatory cytokines in the brain. It crosses the blood-brain barrier and may be neuroprotective in Parkinson's, Amyotrophic lateral sclerosis, Gaucher disease, neuroinflammation, and spinal cord injury. Here we review the CNS effects of ambroxol and its therapeutic potential against neurodegenerative disorders.

Aims of the study were the phytochemical investigation and chemical transformation of isolated compounds of medicinal plant listed in 'Ayurveda' like Dolichandrone atrovirens, endemic to Indian subcontinents. From chloroform extract of D. atrovirens four compounds; Ursolic acid (1), Maslinic acid (2), Lupeol (3), β-sitosterol (4) and from methanol extract five compounds; β-sitosterol-3-O-β-D-glucopyranoside (5), 10-O-trans-p-Methoxycinnamoylcatalpol (6), Kaempferol-3-O-β-D-glucopyranoside (7), 6-O-[6"(S)-hydroxy-2",6"dimethyl-2"(E)-7"-octadienoyl] catalpol (8) and Ixoside (9) were isolated. Ixoside was used for the semi-synthetic modification via azomethine ylide cycloaddition leading to novel spiro-oxindolo-pyrrolizidine adduct. The structures of novel adducts were elucidated by analysis of IR, MS and 1 D/2D NMR data. Furthermore, to confirm the chemo selection of only one double bond, we performed density functional theory (DFT) calculation, which confirms the chemo selectivity. In addition, in-silico ADME studies and atom-additive approach based on SASA was also examined for the molecules which suggest that they may be potential future candidates for drug discovery.

A new metal- and activator-free method for the synthesis of selenoesters from carboxylic acids, Michael acceptors, and selenourea is reported. This is the first reported method for the synthesis of selenoesters directly from carboxylic acids, using selenourea as a nucleophile, source of selenium, and an activator of carbonyl group. A new multifunctional selenourea (source of selenium, activator, base) has been synthesized, tried in a flow reactor to reduce impurity and reaction time.

A new metal-free method for the synthesis of selenoesters directly from carboxylic acids in a flow reactor is reported. The carboxylic acids, Michael acceptors, and bifunctional selenoureas (source of selenium and nucleophile, activator of carbonyl group) were reacted to obtain selenoesters (up to 70% yield). An evidence-backed plausible mechanism is also presented.

Phyllanthus fraternus (PF), a plant from the Euphorbiaceae family, is used extensively in ayurvedic formulations for its significant medicinal properties. When PF is administered alongside conventional drugs, there could be potential herb-drug interactions between the active compounds and the genes involved in drug transport and metabolism. Hence, this study was designed to investigate potential herb-drug interactions, focusing on elucidating their functional and pharmacological mechanisms, using an integrated approach of metabolite profiling and network pharmacology. We utilized LC-MS to generate metabolite profiling of PF and network pharmacology for predicting key targets and pathways. This comprehensive analysis involved the construction of networks illustrating the relationships among compounds, targets, and pathways and the exploration of protein-protein interactions and protein-ligand interactions. In this study, a total of 79 compounds were identified in LC-MS, such as alkaloids, steroids, saponins, flavonoids, lignans, phenolic acids, tannins, terpenoids, and fatty acids. The identified compound's physicochemical properties were predicted using SwissADME. Network analysis predicted 1076 PF-related genes and 1497 genes associated with drug transport and metabolism, identifying 417 overlapping genes, including 51 related to drug transport and metabolism. Based on the degree of interaction the hub targets like ABCB1, CYP1A1, CYP1A2, CYP2C9, and CYP3A4 were identified. In the compound-target-pathway network, 2,4-bis(1,1-dimethyl ethyl)-phenol; 5-Methoxy-N-[(5-Methylpyridin-2-yl) sulfonyl]-1h-Indole-2-Carboxamide; and E,E,Z-1,3,12-Nonadecatriene-5,14-diol possessed more interactions with the targets. This study helps identify bioactive compounds, essential targets, and pathways potentially implicated in these interactions, laying the foundation for future studies (in vitro and in vivo) to verify their potential to explore their clinical implications.Communicated by Ramaswamy H. Sarma.

ATP synthase is a key protein in the oxidative phosphorylation process, as it aids in the effective production of ATP (Adenosine triphosphate) in all life's of kingdoms. ATP synthases have distinctive properties that contribute to efficient ATP synthesis. The ATP synthase of mycobacterium is of special relevance since it has been identified as a target for potential anti-TB molecules, especially Bedaquiline (BDQ). Better knowledge of how mycobacterial ATP synthase functions and its peculiar characteristics will aid in our understanding of bacterial energy metabolism adaptations. Furthermore, identifying and understanding the important distinctions between human ATP synthase and bacterial ATP synthase may provide insight into the design and development of inhibitors that target specific ATP synthase. In recent years, many potential candidates targeting the ATP synthase of mycobacterium have been developed. In this review, we discuss the druggable targets of the Electron transport chain (ETC) and recently identified potent inhibitors (including clinical molecules) from 2015 to 2022 of diverse classes that target ATP synthase of M. tuberculosis.

Tautomerism is an important phenomenon exhibited by many drugs. As we discuss in this review, identifying the different tautomers of drugs and exploring their importance in the mechanisms of drug action are integral components of current drug discovery. Nuclear magnetic resonance (NMR), infrared (IR), ultraviolet (UV), Raman, and terahertz spectroscopic techniques, as well as X-ray diffraction, are useful for exploring drug tautomerism. Quantum chemical methods, in association with pharmacoinformatics tools, are being used to evaluate tautomeric preferences in terms of energy effects. Desmotropy (i.e., tautomeric polymorphism) of the drugs is particularly important in drug delivery studies.

BACKGROUND:Coronavirus disease 2019 (COVID-19) is a potentially fatal disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several studies have shown that hydroxychloroquine (HCQ) significantly inhibits SARS-CoV-2 infections in vitro. OBJECTIVE:Since the phytoconstituents of Cinchona officinalis (CO) are similar to those of HCQ, the objective of this study was to test the antiviral potential of different homeopathic formulations of CO. METHODS:An analysis of the molecular composition of CO was carried out using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry, followed by a detailed docking study. The constituents of CO were docked against various targets of SARS-CoV-2, and the binding potential of the phytoconstituents was compared and quantified. The ligand with the lowest Glide docking score is considered to have the best binding affinity. The cytotoxicity of several homeopathic formulations, including CO mother tincture (CO-MT), was also checked on VeroE6 cells. A known antiviral, remdesivir, was used as a positive control for the in vitro assays to evaluate the effects of CO-MT against SARS-CoV-2-infected VeroE6 cells. RESULTS:Molecular docking studies showed that constituents of CO exhibited binding potential to various targets of SARS-CoV-2, including Mpro, PLpro, RdRp, nucleocapsid protein, ACE2 (in host) and spike protein. Quinoline, one of the constituents of CO, can potentially bind the spike protein of SARS-CoV-2. Quinic acid showed better binding capabilities with Mpro, PLpro RdRp, nucleocapsid protein and ACE2 (allosteric site) than other constituents. Quinidine exhibited better binding to ACE2. Compared to HCQ, other phytoconstituents of CO had the equivalent potential to bind the RNA-dependent RNA polymerase, nucleocapsid protein, Mpro, PLpro and spike protein of SARS-CoV-2. In vitro assays showed that homeopathic CO-MT was not cytotoxic and that CO-MT and remdesivir respectively caused 89% and 99% inhibition of SARS-CoV-2 infection in VeroE6 cells. CONCLUSION:Based on this in silico and in vitro evidence, we propose CO-MT as a promising antiviral medicine candidate for treating COVID-19. In vivo investigation is required to clarify the therapeutic potential of CO-MT in COVID-19.

A novel dehydrogenative C–C bond formation of indoles and N -tosylhydrazones to give di(indolyl)methanes (DIMs) has been demonstrated using tris(pentafluorophenyl)borane as a catalyst.

Thiourea can act as a hydrogen bond donor and as a Bronsted acid catalyst. In this manuscript, Schreiner's thiourea acts as an oxyanion stabilizer for addition of alcohol to [Ir] catalyst is described. Thiourea and [Ir] catalyzed alcohol amination without any base or strong acid is reported. The method was applied for the synthesis of cardiovascular drug ticlopidine.