Structure-based identification of galectin-1 selective modulators in dietary food polyphenols: a pharmacoinformatics approach.

In this study, a set of dietary polyphenols was comprehensively studied for the selective identification of the potential inhibitors/modulators for galectin-1. Galectin-1 is a potent prognostic indicator of tumor progression and a highly regarded therapeutic target for various pathological conditions. This indicator is composed of a highly conserved carbohydrate recognition domain (CRD) that accounts for the binding affinity of ß-galactosides. Although some small molecules have been identified as galectin-1 inhibitors/modulators, there are limited studies on the identification of novel compounds against this attractive therapeutic target. The extensive computational techniques include potential drug binding site recognition on galectin-1, binding affinity predictions of ~ 500 polyphenols, molecular docking, and dynamic simulations of galectin-1 with selective dietary polyphenol modulators, followed by the estimation of binding free energy for the identification of dietary polyphenol-based galectin-1 modulators. Initially, a deep neural network-based algorithm was utilized for the prediction of the druggable binding site and binding affinity. Thereafter, the intermolecular interactions of the polyphenol compounds with galectin-1 were critically explored through the extra-precision docking technique. Further, the stability of the interaction was evaluated through the conventional atomistic 100 ns dynamic simulation study. The docking analyses indicated the high interaction affinity of different amino acids at the CRD region of galectin-1 with the proposed five polyphenols. Strong and consistent interaction stability was suggested from the simulation trajectories of the selected dietary polyphenol under the dynamic conditions. Also, the conserved residue (His44, Asn46, Arg48, Val59, Asn61, Trp68, Glu71, and Arg73) associations suggest high affinity and selectivity of polyphenols toward galectin-1 protein.

Pharmacoinformatics approach based identification of potential Nsp15 endoribonuclease modulators for SARS-CoV-2 inhibition.

In the current study, a structure-based virtual screening paradigm was used to screen a small molecular database against the Non-structural protein 15 (Nsp15) endoribonuclease of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 is the causative agent of the recent outbreak of coronavirus disease 2019 (COVID-19) which left the entire world locked down inside the home. A multi-step molecular docking study was performed against antiviral specific compounds (~8722) collected from the Asinex antiviral database. The less or non-interacting molecules were wiped out sequentially in the molecular docking. Further, MM-GBSA based binding free energy was estimated for 26 compounds which shows a high affinity towards the Nsp15. The drug-likeness and pharmacokinetic parameters of all 26 compounds were explored, and five molecules were found to have an acceptable pharmacokinetic profile. Overall, the Glide-XP docking score and Prime-MM-GBSA binding free energy of the selected molecules were explained strong interaction potentiality towards the Nsp15 endoribonuclease. The dynamic behavior of each molecule with Nsp15 was assessed using conventional molecular dynamics (MD) simulation. The MD simulation information was strongly favors the Nsp15 and each identified ligand stability in dynamic condition. Finally, from the MD simulation trajectories, the binding free energy was estimated using the MM-PBSA method. Hence, the proposed final five molecules might be considered as potential Nsp15 modulators for SARS-CoV-2 inhibition.

Structure-based identification of SARS-CoV-2 main protease inhibitors from anti-viral specific chemical libraries: an exhaustive computational screening approach.

Worldwide coronavirus disease 2019 (COVID-19) outbreak is still threatening global health since its outbreak first reported in the late 2019. The causative novel virus has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 emergent with significant mortality, there is no availability of definite treatment measures. It is now extremely desirable to identify potential chemical entities against SARS-CoV-2 for the treatment of COVID-19. In the present study, a state-of-art virtual screening protocol was implemented on three anti-viral specific chemical libraries against SARS-CoV-2 main protease (Mpro). Particularly, viewing the large-scale biological role of Mpro in the viral replication process it has been considered as a prospective anti-viral drug target. Herein, on collected 79,892 compounds, hierarchical multistep docking followed by relative binding free energy estimation has been performed. Thereafter, implying a user-defined XP-dock and MM-GBSA cut-off scores as -8.00 and -45.00 kcal/mol, chemical space has been further reduced. Exhaustive molecular binding interactions analyses and various pharmacokinetics profiles assessment suggested four compounds (ChemDiv_D658-0159, ChemDiv_F431-0433, Enamine_Z3019991843 and Asinex_LAS_51389260) as potent inhibitors/modulators of SARS-CoV-2 Mpro. In-depth protein-ligand interactions stability in the dynamic state has been evaluated by 100 ns molecular dynamics (MD) simulation studies along with MM-GBSA-based binding free energy estimations of entire simulation trajectories that have revealed strong binding affinity of all identified compounds towards Mpro. Hence, all four identified compounds might be considered as promising candidates for future drug development specifically targeting the SARS-CoV-2 Mpro; however, they also need experimental assessment for a better understanding of molecular interaction mechanisms.

Myricitrin, a Glycosyloxyflavone in Myrica esculenta Bark Ameliorates Diabetic Nephropathy via Improving Glycemic Status, Reducing Oxidative Stress, and Suppressing Inflammation.

The present study evaluated the therapeutic potential of myricitrin (Myr), a glycosyloxyflavone extracted from Myrica esculenta bark, against diabetic nephropathy. Myr exhibited a significant hypoglycemic effect in high fat-fed and a single low-dose streptozotocin-induced type 2 diabetic (T2D) rats. Myr was found to improve glucose uptake by the skeletal muscle via activating IRS-1/PI3K/Akt/GLUT4 signaling in vitro and in vivo. Myr significantly attenuated high glucose (HG)-induced toxicity in NRK cells and in the kidneys of T2D rats. In this study, hyperglycemia caused nephrotoxicity via endorsing oxidative stress and inflammation resulting in the induction of apoptosis, fibrosis, and inflammatory damages. Myr was found to attenuate oxidative stress via scavenging/neutralizing oxidative radicals and improving endogenous redox defense through Nrf-2 activation in both in vitro and in vivo systems. Myr was also found to attenuate diabetes-triggered renal inflammation via suppressing NF-κB activation. Myr inhibited hyperglycemia-induced apoptosis and fibrosis in renal cells evidenced by the changes in the expressions of the apoptotic and fibrotic factors. The molecular docking predicted the interactions between Myr and different signal proteins. An in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) study predicted the drug-likeness character of Myr. Results suggested the possibility of Myr to be a potential therapeutic agent for diabetic nephropathy in the future.

Structure-guided screening of chemical database to identify NS3-NS2B inhibitors for effective therapeutic application in dengue infection.

Dengue infection is the most common arthropod-borne disease caused by dengue viruses, predominantly affecting millions of human beings annually. To find out promising chemical entities for therapeutic application in Dengue, in the current research, a multi-step virtual screening effort was conceived to screen out the entire "screening library" of the Asinex database. Initially, through "Lipinski rule of five" filtration criterion almost 0.6 million compounds were collected and docked with NS3-NS2B protein. Thereby, the chemical space was reduced to about 3500 compounds through the analysis of binding affinity obtained from molecular docking study in AutoDock Vina. Further, the "Virtual Screening Workflow" (VSW) utility of Schrödinger suite was used, which follows a stepwise multiple docking programs such as - high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) docking, and in postprocessing analysis the MM-GBSA based free binding energy calculation. Finally, five potent molecules were proposed as potential inhibitors for the dengue NS3-NS2B protein based on the investigation of molecular interactions map and protein-ligand fingerprint analyses. Different pharmacokinetics and drug-likeness parameters were also checked, which favour the potentiality of selected molecules for being drug-like candidates. The molecular dynamics (MD) simulation analyses of protein-ligand complexes were explained that NS3-NS2B bound with proposed molecules quite stable in dynamic states as observed from the root means square deviation (RMSD) and root means square fluctuation (RMSF) parameters. The binding free energy was calculated using MM-GBSA method from the MD simulation trajectories revealed that all proposed molecules possess such a strong binding affinity towards the dengue NS3-NS2B protein. Therefore, proposed molecules may be potential chemical components for effective inhibition of dengue NS3-NS2B protein subjected to experimental validation.

Rosmarinic Acid Attenuates Cadmium-Induced Nephrotoxicity via Inhibition of Oxidative Stress, Apoptosis, Inflammation and Fibrosis.

The present investigation was executed to reveal the protective mechanism of rosmarinic acid (RA) against cadmium (Cd)-induced nephrotoxicity. RA exhibited a concentration-dependent anti-apoptotic effect against CdCl2 in isolated mouse proximal tubular epithelial cells. Cd treatment significantly (p < 0.01) imparted oxidative stress to the renal cells via excessive ROS production, triggering NO level, NADPH oxidase activation, and impairment of cellular redox defense system. Cd-mediated oxidative stress significantly (p < 0.01) endorsed apoptosis to the murine kidney cells by triggering NF-κB/PKC-δ/TNFR2 activation. In addition, CdCl2 induced renal fibrosis by triggering TGF-ß1/SMAD3/α-SMA/collagen signaling within renal cells. On the other hand, RA significantly (p < 0.05-0.01) attenuated Cd-provoked oxidative stress and associated pathological signal transduction in murine renal cells. RA treatment also could significantly (p < 0.05-0.01) reciprocate Cd-mediated pathological changes in blood and urine parameters in mice. In addition, histological data supported the pharmacological findings. In silico chemometric analyses predicted the possible interactions between RA and different signal proteins and anticipated drug-likeness characteristics of RA. Hence, RA can potentially be applied as a therapeutic agent to treat Cd-mediated nephrotoxicity in future.

Carnosic Acid Attenuates Cadmium Induced Nephrotoxicity by Inhibiting Oxidative Stress, Promoting Nrf2/HO-1 Signalling and Impairing TGF-ß1/Smad/Collagen IV Signalling.

Cadmium (Cd) imparts nephrotoxicity via triggering oxidative stress and pathological signal transductions in renal cells. The present study was performed to explore the protective mechanism of carnosic acid (CA), a naturally occurring antioxidant compound, against cadmium chloride (CdCl2)-provoked nephrotoxicity employing suitable in vitro and in vivo assays. CA (5 µM) exhibited an anti-apoptotic effect against CdCl2 (40 µM) in normal kidney epithelial (NKE) cells evidenced from cell viability, image, and flow cytometry assays. In this study, CdCl2 treatment enhanced oxidative stress by triggering free radical production, suppressing the endogenous redox defence system, and inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activation in NKE cells and mouse kidneys. Moreover, CdCl2 treatment significantly endorsed apoptosis and fibrosis via activation of apoptotic and transforming growth factor (TGF)-ß1/mothers against decapentaplegic homolog (Smad)/collagen IV signalling pathways, respectively. In contrast, CA treatment significantly attenuated Cd-provoked nephrotoxicity via inhibiting free radicals, endorsing redox defence, suppressing apoptosis, and inhibiting fibrosis in renal cells in both in vitro and in vivo systems. In addition, CA treatment significantly (p < 0.05-0.01) restored blood and urine parameters to near-normal levels in mice. Histological findings further confirmed the protective role of CA against Cd-mediated nephrotoxicity. Molecular docking predicted possible interactions between CA and Nrf2/TGF-ß1/Smad/collagen IV. Hence, CA was found to be a potential therapeutic agent to treat Cd-mediated nephrotoxicity.

Identification of Mycobacterium tuberculosis transcriptional repressor EthR inhibitors: Shape-based search and machine learning studies.

Tuberculosis has been a challenge to the world since prehistoric times, and with the advent of drug-resistant strains, it has become more challenging to treat this infection. Ethionamide (ETH), a second-line drug, acts as a prodrug and targets mycolic acid synthesis by targeting the enoyl-acyl carrier protein reductase (InhA) enzyme. Mycobacterium tuberculosis (Mtb) EthR is an ethA gene repressor required to activate prodrug ETH. Recent studies suggest targeting the EthR could lead to newer drug molecules that would help better activate the ETH or complement this process. In this report, we have attempted and successfully identified three new molecules from the drug repurposing library that can target EthR protein and function as ETH boosters. These molecules were obtained after rigorous filtering of the database for their physicochemical, toxicological properties and safety. The molecular docking, molecular dynamics simulations and binding energy studies yielded three compounds, Ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate) (L1), 2-((2,2-Difluorobenzo [d] [1,3]dioxol-5-yl)amino)-2-oxoethyl (E)-3-(5-bromofuran-2-yl)acrylate (L2), and N-(2,3-Dihydrobenzo [b] [1,4]dioxin-6-yl)-4-(2-((4-fluorophenyl)amino)-2-oxoethoxy)-3-methoxy benzamide (L3) are potential EthR inhibitors. We applied machine learning methods to evaluate these molecules for toxicity and synthesisability, suggesting safety and ease of synthesis for these molecules. These molecules are known for other pharmacological activities and can be repurposed faster as adjuvant therapy for tuberculosis.

Fluorene-induced stress in the benthic oligochaete Tubifex tubifex: A multi-biomarker assessment of toxicological pathways and mechanisms under acute and subchronic exposures.

This study examined the multifaceted impacts of fluorene exposure on Tubifex tubifex, encompassing acute (survival analysis and behavioral responses) and subchronic exposure regimens (antioxidant enzyme response and histopathology), molecular docking studies, and generalized read-across analysis. Survival analysis revealed concentration-dependent increases in toxicity over varying time intervals, with LC50 values decreasing from 30.072 mg/L at 24 h to 12.365 mg/L at 96 h, emphasizing the time-sensitive and concentration-responsive nature of the stressor. Behavioral responses were both concentration- and duration-dependent. While Erratic Movement and Clumping Tendency exhibited earlier responses (within 24 h) at lower concentrations, the wrinkling effect and mucus secretion) exhibited delayed onset, suggesting intricate regulatory mechanisms underlying adaptability to environmental challenges; moreover, the wrinkling effect was consistently induced at higher concentrations, indicating greater sensitivity to the toxic effects of fluorene. With sublethal environmentally relevant concentrations-1.24 mg/l and 2.47 mg/L i.e., 10% and 20% 96 h, respectively-the antioxidant enzyme response (i.e., upregulation of SOD, CAT, and GST) with increasing fluorene concentration, revealing a nonlinear, hormetic response, suggested adaptive protection at lower doses but inhibition at higher concentrations. Histopathological examination indicated that higher fluorene concentrations caused cellular proliferation, inflammation, and severe tissue damage in the digestive tract and body wall. Molecular docking studies demonstrated robust interactions between fluorene and major stress biomarker enzymes, disrupting their functions and inducing oxidative stress. Interactions with cytochrome c oxidase suggested interference with cellular energy production. Generalized Read-Across (GenRA) analysis unveiled shared toxicity mechanisms among fluorene and its analogs, involving the formation of reactive epoxides and the influence of cytochrome P450 enzymes. The diverse functional groups of these analogs, particularly chlorine-containing compounds, were implicated in toxicity through lipid peroxidation and membrane damage. Adverse outcome pathways and broader consequences for aquatic ecosystem health are discussed.

Machine learning assisted methods for the identification of low toxicity inhibitors of Enoyl-Acyl Carrier Protein Reductase (InhA).

Tuberculosis (TB) is one of the life-threatening infectious diseases with prehistoric origins and occurs in almost all habitable parts of the world. TB mainly affects the lungs, and its etiological agent is Mycobacterium tuberculosis (Mtb). In 2022, more than 10 million people were infected worldwide, and 1.3 million were children. The current study considered the in-silico and machine learning (ML) approaches to explore the potential anti-TB molecules from the SelleckChem database against Enoyl-Acyl Carrier Protein Reductase (InhA). Initially, the entire database of ∼ 119000 molecules was sorted out through drug-likeness. Further, the molecular docking study was conducted to reduce the chemical space. The standard TB drug molecule's binding energy was considered a threshold, and molecules found with lower affinity were removed for further analyses. Finally, the molecules were checked for the pharmacokinetic and toxicity studies, and compounds found to have acceptable pharmacokinetic parameters and were non-toxic were considered as final promising molecules for InhA. The above approach further evaluated five molecules for ML-based toxicity and synthetic accessibility assessment. Not a single molecule was found toxic and each of them was revealed as easy to synthesise. The complex between InhA and proposed and standard molecules was considered for molecular dynamics simulation. Several statistical parameters showed the stability between InhA and the proposed molecule. The high binding affinity was also found for each of the molecules towards InhA using the MM-GBSA approach. Hence, the above approaches and findings exposed the potentiality of the proposed molecules against InhA.

Structure-guided screening of protein-protein interaction for the identification of Myc-Max heterodimer complex modulators.

De-regulation of oncogenic myelocytomatosis (c-Myc or Myc) transcription factor is one of the most common molecular anomalies encountered in human cancers, and it is typically linked to many aggressive malignancies including breast, lung, cervix, colon glioblastomas, and other haematological organs. The Myc belongs to the basic helix-loop-helix zipper protein family (bHLH-ZIP), and its dimerization with another principal interactor protein partner Myc-associated factor X (Max) is essentially required for cellular transformation, cell growth and proliferation, and transcriptional activation. Intermolecular interactions have been evaluated between hetero-dimer Myc-Max protein, which identified protein-protein interaction (PPI) specific modulators using highly précised molecular docking study followed by long-range interaction stability analyzed through molecular dynamic (MD) simulation. Moreover, ADME profile analyses have been estimated for screened hit compounds. MM-GBSA-based binding free energy (ΔG) estimations have been performed for all screened hit compounds obtained from multi-step molecular docking-based virtual screening technique. According to the employed various rigorous multi-chemometric techniques, four identified inhibitors/modulators appear to have a considerable number of intermolecular contacts with hotspot residues in the hetero-dimer interface region of the Myc-Max PPI complex. However, identified hit compounds might need further structural optimization or extensive biophysical analyses for better understanding of the molecular mechanism for exhibiting the Myc-Max PPI interface binding stability.Communicated by Ramaswamy H. Sarma.

Investigation of bio-active Amaryllidaceae alkaloidal small molecules as putative SARS-CoV-2 main protease and host TMPRSS2 inhibitors: interpretation by in-silico simulation study.

The novel coronavirus disease 2019 (Covid-19) outburst is still threatening global health. This highly contagious viral disease is caused by the infection of SARS-CoV-2 virus. Covid-19 and post-Covid-19 complications induce noteworthy mortality. Potential chemical hits and leads against SARS-CoV-2 for combating Covid-19 are urgently required. In the present study, a virtual-screening protocol was executed on potential Amaryllidaceae alkaloids from a pool of natural compound library against SARS-CoV-2 main protease (Mpro) and transmembrane serine protease (TMPRSS2). For the collected 1016 alkaloids from the curated library, initially, molecular docking using AutoDock Vina (ADV), and thereafter 100 ns molecular-dynamic (MD) simulation has been executed for the best top-ranked binding affinity compounds for both the viral and host proteins. Comprehensive intermolecular-binding interactions profile of Amaryllidaceae alkaloids suggested that phyto-compounds Galantamine, Lycorenine, and Neronine as potent modulators of SARS-CoV-2 Mpro and host TMPRSS2 protein. All atomistic long range 100 ns MD simulation studies of each top ranked complex in triplicates also illustrated strong binding affinity of three compounds towards Mpro and TMPRSS2. Identified compounds might be recommended as prospective anti-viral agents for future drug development selectively targeting the SARS-CoV-2 Mpro or blocking host TMPRSS2 receptor, subjected to pre-clinical and clinical assessment for a better understanding of in-vitro molecular interaction and in-vivo validation.Communicated by Ramaswamy H. Sarma.

Exploring CIP2A modulators using multiple molecular modeling approaches.

Like other human oncoproteins, Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) exerts cancer promoting function through interaction with other partner proteins, such as MYC and Protein Phosphatase 2A (PP2A). CIP2A regulates several MYC-independent and/or dependent gene expression programs. Broadly, CIP2A can inhibit PP2A, and especially it has been shown to inhibit MYC-associated PP2A, precisely to increase MYC stability and function. Availability of crystal structure has broached the research focus to develop new therapeutics targeting CIP2A. In the present study, structural information of the protein has been used for identification of modulators for homo-dimer CIP2A using advanced structure-based drug design approaches. The compound library, 'Maybridge Screening Collection' database (∼62,000 compounds) has been virtually screened to find out potent modulators for CIP2A. Identification of hotspot region on CIP2A protein-protein interaction interface has been performed using three different tools (HotPoint, SiteMap and icmPocketFinder). Thereafter, molecular docking (Extra Precision and Induced Fit Docking), and long range molecular dynamics simulation analysis, and ADME profile analysis have been carried out for screening purposes. Calculations of MM-PBSA based binding free energy (ΔG), and Density Functional Theory for quantum chemical simulations have been carried out for the hit compounds obtained through multi-step molecular docking based virtual screening technique. The multi-chemometric studies suggested that hit modulators have formed significant numbers of molecular interactions with hotspot residues in the homo-dimer interface region, which enable to hold CIP2A binding stability. Compounds with average ΔG values (ranging -3.4 x 10-2 to -1.1 x 10-2 KJ/mol) signifying promising CIP2A modulators.Communicated by Ramaswamy H. Sarma.

Quercetin: a silent retarder of fatty acid oxidation in breast cancer metastasis through steering of mitochondrial CPT1.

BACKGROUND: Recent evidence confirmed that the maximum energy in metastatic breast cancer progression is supplied by fatty acid oxidation (FAO) governed by a rate-limiting enzyme, carnitine palmitoyltransferase 1 (CPT1). Therefore, the active limitation of FAO could be an emerging aspect to inhibit breast cancer progression. Herein, for the first time, we have introduced quercetin (QT) from a non-dietary source (Mikania micrantha Kunth) to limit the FAO in triple-negative breast cancer cells (TNBC) through an active targeting of CPT1. METHODS: Molecular quantification of QT was confirmed through high-performance thin-layer chromatography (HPTLC). Computational docking analyses predicted the binding affinity of QT to CPT1. Cell-based seahorse energy efflux investigated the mitochondrial respiration rate, glycolytic function and ATP production rate. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) investigated the FAO-associated gene expression. Matrigel cell invasion and fluorescence-activated cell sorting analyses investigated anti-metastatic and apoptotic cell death induction activities, respectively. In vivo antitumor activities were checked using the female breast cancer mice (BALB/c) model. RESULTS: QT resulted in a significant reduction in the intracellular mitochondrial respiration and glycolytic function, limiting extensive ATP production. In turn, QT elevated the reactive oxygen species (ROS) and depleted antioxidant levels to induce anti-metastatic and cell apoptosis activities. qRT-PCR resulted in active healing of altered FAO-associated gene expression which was well predicted through the successful in silico molecular binding potentiality of QT to CPT1. Subsequently, QT has shown excellent in vivo antitumor activities through the altered lipid profile and oxidative stress-healing capabilities. CONCLUSIONS: All the obtained data significantly grounded the fact that QT could be a promising metabolism-targeted breast cancer therapeutic.

Identification of bio-active food compounds as potential SARS-CoV-2 PLpro inhibitors-modulators via negative image-based screening and computational simulations.

Despite significant studies on the COVID-19 pandemic, scientists around the world are still battling to find a definitive therapy against the ongoing severe global health crisis. In this study, advanced computational approaches have been employed to identify bioactive food constituents as potential SARS-CoV-2 PLpro inhibitors-modulators. As a validated antiviral drug target, PLpro has gained tremendous attention for therapeutics developments. Therefore, targeting the multifunctional SARS-CoV-2 PLpro protein, ∼1039 bioactive dietary compounds have been screened extensively through novel techniques like negative image-based (NIB) screening and molecular docking approaches. In particular, the three different models of NIB screening have been generated and used to re-score the dietary compounds based on the negative image which is created by reversing the shape and electrostatics features of PLpro protein's ligand-binding cavity. Further, 100 ns molecular dynamics simulation has been performed and MM-GBSA based binding free energies have been estimated for the final proposed four dietary compounds (PC000550, PC000361, PC000558, and PC000573) as potential inhibitors/modulators of SARS-CoV-2 PLpro protein. Employed computational study outcome also has been compared with respect to the earlier experimentally investigated compound GRL0617 against SARS-CoV-2 PLpro protein, which suggests much greater interaction potential in terms of binding affinity and other energetic contributions for the proposed dietary compounds. Hence, the present study suggests that proposed dietary compounds can be suitable chemical entities for modulating the activity of PLpro protein or can be further utilized for optimizing or screening of novel chemical surrogates, however also needs experimental evaluation for entry in clinical studies for better assessment.

In silico identification of small molecule modulators for disruption of Hsp90-Cdc37 protein-protein interaction interface for cancer therapeutic application.

The protein-protein interactions (PPIs) in the biological systems are important to maintain a number of cellular processes. Several disorders including cancer may be developed due to dysfunction in the assembly of PPI networks. Hence, targeting intracellular PPIs can be considered as a crucial drug target for cancer therapy. Among the enormous and diverse group of cancer-enabling PPIs, the Hsp90-Cdc37 is prominent for cancer therapeutic development. The successful inhibition of Hsp90-Cdc37 PPI interface can be an important therapeutic option for cancer management. In the current study, a set of more than sixty thousand compounds belong to four databases were screened through a multi-steps molecular docking study in Glide against the Hsp90-Cdc37 interaction interface. The Glide-score and Prime-MM-GBSA based binding free energy of DCZ3112, standard Hsp90-Cdc37 inhibitor were found to be -6.96 and -40.46 kcal/mol, respectively. The above two parameters were used as cut-off score to reduce the chemical space from all successfully docked molecules. Furthermore, the in-silico pharmacokinetics parameters, common-feature pharmacophore analyses and the molecular binding interactions were used to wipe out the inactive molecules. Finally, four molecules were found to be important to modulate the Hsp90-Cdc37 interface. The potentiality of the final four molecules was checked through several drug-likeness characteristics. The molecular dynamics (MD) simulation study explained that all four molecules retained inside the interface of Hsp90-Cdc37. The binding free energy of each molecule obtained from the MD simulation trajectory was clearly explained the strong affection towards the Hsp90-Cdc37. Hence, the proposed molecule might be crucial for successful inhibition of the Hsp90-Cdc37 interface.Communicated by Ramaswamy H. Sarma.

Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches.

The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein.

Carnosic acid attenuates doxorubicin-induced cardiotoxicity by decreasing oxidative stress and its concomitant pathological consequences.

This work aimed to reveal the protective mechanism of CA against Dox (doxorubicin)-induced cardiotoxicity. In isolated murine cardiomyocytes, CA showed a concentration-dependent cytoprotective effect against Dox. Dox treatment significantly (p < 0.01) increased the formation of reactive oxygen species (ROS), increased NO levels, activated NADPH oxidase, and inactivated the cellular redox defense mechanism in cardiac cells, resulting in augmented oxidative stress in cardiomyocytes and rat hearts. Dox-induced oxidative stress significantly (p < 0.01) upregulated several pathogenic signal transductions, which induced apoptosis, inflammation, and fibrosis in cardiomyocytes and murine hearts. In contrast, CA significantly (p < 0.05-0.01) reciprocated Dox-induced cardiac apoptosis, inflammation, and fibrosis by suppressing oxidative stress and interfering with pathological signaling events in both isolated murine cardiomyocytes and rat hearts. CA treatment significantly (p < 0.05-0.01) countered Dox-mediated pathological changes in blood parameters in rats. Histological examinations backed up the pharmacological findings. In silico chemometric investigations predicted potential interactions between CA and studied signal proteins, as well as the drug-like features of CA. Thus, it would be concluded that CA has the potential to be regarded as an effective agent to alleviate Dox-mediated cardiotoxicity in the future.

Insight into the screening of potential beta-lactamase inhibitors as anti-bacterial chemical agents through pharmacoinformatics study.

Drug resistance is an unsolved and major concern in the bacterial infection. Continuous development of drug-resistance to the antibiotics exponentially rises the danger of bacterial infections. Chemical components from the plants are becoming a major resource of potentially effective therapeutic chemical agents for the wide range of diseases including bacterial infections. In the current study, pharmacoinformatics methodologies were implemented on more than two hundred known phytochemicals to find promising beta-lactamase inhibitors for therapeutically effective anti-bacterial agents. Initially, the molecular docking-based score was used to reduce the chemical space of the selected dataset. Fourteen molecules were found to have more affinity towards the beta-lactamase in compared to the well-known anti-bacterial agent, Avibactam. Binding interactions analysis revealed the strong binding interactions between phytochemicals and catalytic amino residues. For further analysis, molecular dynamics (MD) simulations, density functional theory (DFT) and in silico pharmacokinetics studies were performed. Parameters from MD simulations studies suggested that selected molecules are strong enough to retain in the active site in different orientations of the beta-lactamase. The orbital energies obtained from the DFT study was undoubtedly explained the potentiality of the selected compounds for being effective beta-lactamase inhibitors. The drug-likeness and acceptable pharmacokinetics parameters were observed using in silico ADME analysis. Therefore, observations from the multiple pharmacoinformatics approach explained without any doubt that selected molecules are potential enough being promising anti-bacterial compounds. [Formula: see text] Communicated by Ramaswamy H. Sarma.

Multi-step molecular docking and dynamics simulation-based screening of large antiviral specific chemical libraries for identification of Nipah virus glycoprotein inhibitors.

Nipah virus (NiV) infections are highly contagious and can cause severe febrile encephalitis. An outbreak of NiV infection has reported high mortality rates in Southeast Asian countries including Bangladesh, East Timor, Malaysia, Papua New Guinea, Vietnam, Cambodia, Indonesia, Madagascar, Philippines, Thailand and India. Considering the high risk for an epidemic outbreak, the World Health Organization (WHO) declared NiV as an emerging priority pathogen. However, there are no effective therapeutics or any FDA approved drugs available for the treatment of this infection. Among the known nine proteins of NiV, glycoprotein plays an important role in initiating the entry of viruses and attaching to the host cell receptors. Herein, three antiviral databases consisting of 79,892 chemical entities have been computationally screened against NiV glycoprotein (NiV-G). Particularly, multi-step molecular docking followed by extensive molecular binding interactions analyses, binding free energy estimation, in silico pharmacokinetics, synthetic accessibility and toxicity profile evaluations have been carried out for initial identification of potential NiV-G inhibitors. Further, molecular dynamics (MD) simulation has been performed to understand the dynamic properties of NiV-G protein-bound with proposed five inhibitors (G1-G5) and their interactions behavior, and any conformational changes in NiV-G protein during simulations. Moreover, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) based binding free energies (∆G) has been calculated from all MD simulation trajectories to understand the energy contribution of each proposed compound in maintaining and stabilizing the complex binding interactions with NiV-G protein. Proposed compounds showed high negative ∆G values ranging from -166.246 to -226.652 kJ/mol indicating a strong affinity towards the NiV-G protein.