Screening of bioactive compounds from selected mushroom species against putative drug targets in Mycobacterium tuberculosis: a multi-target approach.

Mycobacterium tuberculosis (Mtb) is a notorious pathogen that causes one of the highest mortalities globally. Due to a pressing demand to identify novel therapeutic alternatives, the present study aims to focus on screening the putative drug targets and prioritizing their role in antibacterial drug development. The most vital proteins involved in the Biotin biosynthesis pathway and the Lipoarabinomannan (LAM) pathway such as biotin synthase (bioB) and alpha-(1->6)-mannopyranosyltransferase A (mptA) respectively, along with other essential virulence proteins of Mtb were selected as drug targets. Among these, the ones without native structures were modelled and validated using standard bioinformatics tools. Further, the interactions were performed with naturally available lead molecules present in selected mushroom species such as Agaricus bisporus, Pleurotus djamor, Hypsizygus ulmarius. Through Gas Chromatography-Mass Spectrometry (GC-MS), 15 bioactive compounds from the methanolic extract of mushrooms were identified. Further, 4 were selected based on drug-likeness and pharmacokinetic screening for molecular docking analysis against our prioritized targets wherein Benz[e]azulene from Pleurotus djamor illustrated a good binding affinity with a LF rank score of -9.036 kcal mol -1 against nuoM (NADH quinone oxidoreductase subunit M) and could be used as a prospective candidate in order to combat Tuberculosis (TB). Furthermore, the stability of the complex are validated using MD Simulations and subsequently, the binding free energy was calculated using MM-GBSA analysis. Thus, the current in silico analysis suggests a promising role of compounds extracted from mushrooms in tackling the TB burden.Communicated by Ramaswamy H. Sarma.

Computational screening of potential anti-inflammatory leads from Jeevaneeya Rasayana plants targeting COX-2 and 5- LOX by molecular docking and dynamic simulation approaches.

Inflammation plays a pivotal role in various pathological processes, ranging from routine injuries and infections to cancer. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) are two major enzymes involved in the formation of lipid mediators of inflammation, such as prostaglandins and leukotrienes, through the arachidonic acid pathway. Despite the frequent use of nonsteroidal anti-inflammatory drugs for managing inflammatory disorders by inhibiting these enzymes, there is a wide spectrum of adverse effects linked to their usage. Jeevaneeya Rasayana (JR), a polyherbal formulation traditionally used in India, is renowned for its anti-inflammatory properties. The present study aimed to identify the potential phytocompounds in JR plants against COX-2 and 5-LOX, utilizing molecular docking and dynamic simulations. Among the 429 identified phytocompounds retrieved from publicly available data sources, Terrestribisamide and 1-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine have shown potential binding affinity and favorable interactions with COX-2 and 5-LOX arachidonic acid binding sites. The physicochemical properties and ADMET profiles of these compounds determined their drug-likeness and pharmacokinetics features. Additional validation using molecular dynamics simulations, SASA, Rg, and MM-PBSA binding energy calculations affirmed the stability of the complex formed between those compounds with target proteins. Together, the study identified the effectual binding potential of those bioactive compounds against COX-2 and 5-LOX, providing a viable approach for the development of effective anti-inflammatory medications.

Immunoinformatic exploration of a multi-epitope-based peptide vaccine candidate targeting emerging variants of SARS-CoV-2.

Many countries around the world are facing severe challenges due to the recently emerging variants of SARS-CoV-2. Over the last few months, scientists have been developing treatments, drugs, and vaccines to subdue the virus and prevent its transmission. In this context, a peptide-based vaccine construct containing pathogenic proteins of the virus known to elicit an immune response was constructed. An analysis of the spike protein-based epitopes allowed us to design an "epitope-based subunit vaccine" against coronavirus using the approaches of "reverse vaccinology" and "immunoinformatics." Computational experimentation and a systematic, comprehensive protocol were followed with an aim to develop and design a multi-epitope-based peptide (MEBP) vaccine candidate. Our study attempted to predict an MEBP vaccine by introducing mutations of SARS-CoV-2 (Delta, Lambda, Iota, Omicron, and Kappa) in Spike glycoprotein and predicting dual-purpose epitopes (B-cell and T-cell). This was followed by screening the selected epitopes based on antigenicity, allergenicity, and population coverage and constructing them into a vaccine by using linkers and adjuvants. The vaccine construct was analyzed for its physicochemical properties and secondary structure prediction, and a 3D structure was built, refined, and validated. Furthermore, the peptide-protein interaction of the vaccine construct with Toll-like receptor (TLR) molecules was performed. Immune profiling was performed to check the immune response. Codon optimization of the vaccine construct was performed to obtain the GC content before cloning it into the E. coli genome, facilitating its progression it into a vector. Finally, an in-silico simulation of the vaccine-protein complex was performed to comprehend its stability and conformational behavior.

BRCA1/TP53 tumor proteins inhibited by novel analogues of curcumin - Insight from computational modelling, dynamic simulation and experimental validation.

The current study aimed to design novel curcumin analogue inhibitors with antiproliferative and antitumor activity towards BRCA1 and TP53 tumor proteins and to study their therapeutic potential by computer-aided molecular designing and experimental investigations. Four curcumin analogues were computationally designed and their drug-likeness and pharmacokinetic properties were predicted. The binding of these analogues against six protein targets belonging to BRCA1 and TP53 tumor proteins were modelled by molecular docking and their binding energies were compared with that of curcumin and the standard drug cyclophosphamide and its validated target. The stabilities of selected docked complexes were confirmed by molecular dynamic simulation (MDS) and MMGBSA calculations. The best-docked analogue was chemically synthesized, characterized, and used for in vitro cytotoxic screening using DLA, EAC, and C127I cell lines. In vivo antitumor studies were carried out in Swiss Albino Mice. The study revealed that the designed analogues satisfied drug-likeness and pharmacokinetic properties and demonstrated better binding affinity to the selected targets than curcumin. Among the analogues, NLH demonstrated significant interaction with the BRCA1-BRCT-c domain (TG3; binding energy -8.3 kcal/mol) when compared to the interaction of curcumin (binding energy -6.19 kcal) and cyclophosphamide (binding energy -3.8 kcal/mol) and its usual substrate (TG7). The MDS and MM/GBSA studies revealed that the binding free energy of the NLH-TG3 complex (-61.24 kcal/mol) was better when compared to that of the cyclophosphamide-TG7 complex (-21.67 kcal/mol). In vitro, cytotoxic studies showed that NLH demonstrated significant antiproliferative activities against tumor cell lines. The in vivo study depicted NLH possesses the potential for tumor inhibition. Thus, the newly synthesized curcumin analogue is probably used to develop novel therapeutic agents against breast cancer.

The escalated potential of the novel isolate Bacillus cereus NJD1 for effective biodegradation of LDPE films without pre-treatment.

This study focused on the biodegradation of LDPE films using a novel isolate of Bacillus obtained from soil samples collected from a 20-year-old plastic waste dump. The aim was to evaluate the biodegradability of LDPE films treated with this bacterial isolate. The results indicated a 43% weight loss of LDPE films within 120 days of treatment. The biodegradability of LDPE films was confirmed through various testing methods, including BATH, FDA, CO2 evolution tests, and changes in total cell growth count, protein content, viability, pH of the medium, and release of microplastics. The bacterial enzymes, including laccases, lipases, and proteases, were also identified. SEM analysis revealed biofilm formation and surface changes in treated LDPE films, while EDAX analysis showed a reduction in carbon elements. AFM analysis demonstrated differences in roughness compared to the control. Furthermore, wettability increased and tensile strength decreased, confirming the biodegradation of the isolate. FTIR spectral analysis showed changes in skeletal vibrations, such as stretches and bends, in the linear structure of polyethylene. FTIR imaging and GC-MS analysis also confirmed the biodegradation of LDPE films by the novel isolate identified as Bacillus cereus strain NJD1. The study highlights the potentiality of the bacterial isolate for safe and effective microbial remediation of LDPE films.

Carboxymuconolactone decarboxylase is a prospective molecular target for multi-drug resistant Acinetobacter baumannii-computational modeling, molecular docking and dynamic simulation studies.

Multidrug-resistant Acinetobacter baumannii (MDRAb), a priority-I pathogen declared by the World Health Organization, became a potential healthcare concern worldwide with a high mortality rate. Thus, the identification of putative molecular targets and potential lead molecules is an important concern in healthcare. The present study aimed to screen a prospective molecular target and effectual binders for the drug discovery of MDRAb by computational virtual screening approach. Based on the functional role, γ-carboxymuconolactone decarboxylase (CMD) was prioritized as the target and its three-dimensional (3D) structure was computationally modeled. Based on the availability of the 3D structure, twenty-five herbal molecules were selected by database search, and their drug-likeliness, pharmacokinetic, and toxicity features were predicted. The effectual binding of the selected molecules towards CMD was predicted by molecular docking. The stability of the best-docked complexes was predicted by molecular dynamics (MD) simulation for 100 ns and binding energy calculations were carried out by molecular mechanics generalized Born and surface area solvation (MM/GBSA) method. Out of twenty-five molecules screened, hirsutine (an indole alkaloid of Uncaria rhynchophylla) and thymoquinone (a phytochemical of Nigella sativa) were qualified for drug likeliness, pharmacokinetic, and toxicity features and demonstrated significant effectual binding to CMD when compared with the binding of co-crystallized inhibitor and CMD (control). The docked complexes of hirsutine and thymoquinone, and CMD were stabilized by the binding energies of -8. 30 and -8. 46 kcal/mol respectively. These molecules were qualified in terms of ideal drug likeliness, ADME, and toxicity properties. MD simulation studies showed that the ligand-protein complexes were stable throughout the simulation. The binding free energies of the complexes by MMGBSA were estimated to be -42.08157745 kcal/mol and -36.58618242 kcal/mol for hirsutine and thymoquinone respectively when compared with the calculated binding free energy of the control (-28.75032666 kcal/mol). This study concluded that hirsutine and thymoquinone can act as potential lead molecules against CMD and the present hypothesis can be scaled up to develop potential inhibitors against MDRAb.

Computational design of prospective molecular targets for Burkholderia cepacia complex by molecular docking and dynamic simulation studies.

The study aimed to screen prospective molecular targets of BCC and potential natural lead candidates as effective binders by computational modeling, molecular docking, and dynamic (MD) simulation studies. Based on the virulent functions, tRNA 5-methylaminomethyl-2-thiouridine biosynthesis bifunctional protein (mnmC) and pyrimidine/purine nucleoside phosphorylase (ppnP) were selected as the prospective molecular targets. In the absence of experimental data, the three-dimensional (3D) structures of these targets were computationally predicted. After a thorough literature survey and database search, the drug-likeness, and pharmacokinetic properties of 70 natural molecules were computationally predicted and the effectual binding of the best lead molecules against both the targets was predicted by molecular docking. The stabilities of the best-docked complexes were validated by MD simulation and the binding energy calculations were carried out by MM-GBSA approaches. The present study revealed that the hypothetical models of mnmC and ppnP showed stereochemical accuracy. The study also showed that among 70 natural compounds subjected to computational screening, Honokiol (3',5-Di(prop-2-en-1-yl) [1,1'-biphenyl]-2,4'-diol) present in Magnolia showed ideal drug-likeness, pharmacokinetic features and showed effectual binding with mnmC and ppnP (binding energies -7.3 kcal/mol and -6.6 kcal/mol, respectively). The MD simulation and GBSA calculation studies showed that the ligand-protein complexes stabilized throughout tMD simulation. The present study suggests that Honokiol can be used as a potential lead molecule against mnmC and ppnP targets of BCC and this study provides insight into further experimental validation for alternative lead development against drug resistant BCC.

Correction to: Scope of repurposed drugs against the potential targets of the latest variants of SARS-CoV-2.

[This corrects the article DOI: 10.1007/s11224-022-02020-z.].

Scope of repurposed drugs against the potential targets of the latest variants of SARS-CoV-2.

The unprecedented outbreak of the severe acute respiratory syndrome (SARS) Coronavirus-2, across the globe, triggered a worldwide uproar in the search for immediate treatment strategies. With no specific drug and not much data available, alternative approaches such as drug repurposing came to the limelight. To date, extensive research on the repositioning of drugs has led to the identification of numerous drugs against various important protein targets of the coronavirus strains, with hopes of the drugs working against the major variants of concerns (alpha, beta, gamma, delta, omicron) of the virus. Advancements in computational sciences have led to improved scope of repurposing via techniques such as structure-based approaches including molecular docking, molecular dynamic simulations and quantitative structure activity relationships, network-based approaches, and artificial intelligence-based approaches with other core machine and deep learning algorithms. This review highlights the various approaches to repurposing drugs from a computational biological perspective, with various mechanisms of action of the drugs against some of the major protein targets of SARS-CoV-2. Additionally, clinical trials data on potential COVID-19 repurposed drugs are also highlighted with stress on the major SARS-CoV-2 targets and the structural effect of variants on these targets. The interaction modelling of some important repurposed drugs has also been elucidated. Furthermore, the merits and demerits of drug repurposing are also discussed, with a focus on the scope and applications of the latest advancements in repurposing.

Understanding the Xylooligosaccharides Utilization Mechanism of Lactobacillus brevis and Bifidobacterium adolescentis: Proteins Involved and Their Conformational Stabilities for Effectual Binding.

Xylooligosaccharides having various degrees of polymerization such as xylobiose, xylotriose, and xylotetraose positively affect human health by interacting with gut proteins. The present study aimed to identify proteins present in gut microflora, such as xylosidase, xylulokinase, etc., with the help of retrieved whole-genome annotations and find out the mechanistic interactions of those with the above substrates. The 3D structures of proteins, namely Endo-1,4-beta-xylanase B (XynB) from Lactobacillus brevis and beta-D-xylosidase (Xyl3) from Bifidobacterium adolescentis, were computationally predicted and validated with the help of various bioinformatics tools. Molecular docking studies identified the effectual binding of these proteins to the xylooligosaccharides, and the stabilities of the best-docked complexes were analyzed by molecular dynamic simulation. The present study demonstrated that XynB and Xyl3 showed better effectual binding toward Xylobiose with the binding energies of - 5.96 kcal/mol and - 4.2 kcal/mol, respectively. The interactions were stabilized by several hydrogen bonding having desolvation energy (- 6.59 and - 7.91). The conformational stabilities of the docked complexes were observed in the four selected complexes of XynB-xylotriose, XynB-xylotetraose, Xyl3-xylobiose, and Xyn3-xylotriose by MD simulations. This study showed that the interactions of these four complexes are stable, which means they have complex metabolic activities among each other. Extending these studies of understanding, the interaction between specific probiotics enzymes and their ligands can explore the detailed design of synbiotics in the future.

Recent advances in plastic degradation - From microbial consortia-based methods to data sciences and computational biology driven approaches.

The conventional methods of plastic waste management such as mechanical and chemical recycling, landfill complemented by incineration and pyrosis have limited scope. Thus, microbiological-based approaches by the application of microbial consortia or cocultures are appropriate, cost-effective, and eco-friendly to manage plastic wastes. Screening of novel plastic degrading microorganisms, the formulation of microbial consortia, and utilisation of their enzymes probably play a role in plastic waste management. The by-products of microbial degradation of plastic waste can be used as bio-energy sources, that aids in the development of cost-effective bio-digesters. The recent advancements in computational biology and bioinformatics play a vital role in understanding the molecular basis of enzymatic degradation of plastic polymers by microorganisms. Understanding the three-dimensional structures of plastic degrading enzymes and their metabolic pathways play a vital role in studying the microbial degradation of plastics. The present review highlights the scope of various microorganisms and their enzymes in plastic degradation. The review emphasizes the applications of co-cultures or microbial consortia-based approaches for the enhanced degradation of plastic polymers and the production of value-added end products that can be used as the prototypes of bioenergy sources. The review also provides a comprehensive outlook on the applications of data sciences, computational biology, and bioinformatics resources, and web-based tools towards the study of microbial degradation of plastic polymers.

Carbon fullerene and nanotube are probable binders to multiple targets of SARS-CoV-2: Insights from computational modeling and molecular dynamic simulation studies.

The present study aimed to predict the binding potential of carbon nanotube and nano fullerene towards multiple targets of SARS-CoV-2. Based on the virulent functions, the spike glycoprotein, RNA-dependent RNA polymerase, main protease, papain-like protease, and RNA binding domain of the nucleocapsid proteins of SARS-CoV-2 were prioritized as the molecular targets and their three-dimensional (3D) structures were retrieved from the Protein Data Bank. The 3D structures of carbon nanotubes and nano-fullerene were computationally modeled, and the binding potential of these nanoparticles to the selected molecular targets was predicted by molecular docking and molecular dynamic (MD) simulations. The drug-likeness and pharmacokinetic features of the lead molecules were computationally predicted. The current study suggested that carbon fullerene and nanotube demonstrated significant binding towards the prioritized multi-targets of SARS-CoV-2. Interestingly, carbon nanotube showed better interaction with these targets when compared to carbon fullerene. MD simulation studies clearly showed that the interaction of nanoparticles and selected targets possessed stability and conformational changes. This study revealed that carbon nanotubes and fullerene are probably used as effectual binders to multiple targets of SARS-CoV-2, and the study offers insights into the experimental validation and highlights the relevance of utilizing carbon nanomaterials as a therapeutic remedy against COVID-19.

Structural insights on the interaction potential of natural leads against major protein targets of SARS-CoV-2: Molecular modelling, docking and dynamic simulation studies.

Though significant efforts are in progress for developing drugs and vaccines against COVID-19, limited therapeutic agents are available currently. Thus, it is essential to undertake COVID-19 research and to identify therapeutic interventions in which computational modeling and virtual screening of lead molecules provide significant insights. The present study aimed to predict the interaction potential of natural lead molecules against prospective protein targets of SARS-CoV-2 by molecular modeling, docking, and dynamic simulation. Based on the literature survey and database search, fourteen molecular targets were selected and the three targets which lack the native structures were computationally modeled. The drug-likeliness and pharmacokinetic features of ninety-two natural molecules were predicted. Four lead molecules with ideal drug-likeliness and pharmacokinetic properties were selected and docked against fourteen targets, and their binding energies were compared with the binding energy of the interaction between Chloroquine and Hydroxychloroquine to their usual targets. The stabilities of selected docked complexes were confirmed by MD simulation and energy calculations. Four natural molecules demonstrated profound binding to most of the prioritized targets, especially, Hyoscyamine and Tamaridone to spike glycoprotein and Rotiorinol-C and Scutifoliamide-A to replicase polyprotein-1ab main protease of SARS-CoV-2 showed better binding energy, conformational and dynamic stabilities compared to the binding energy of Chloroquine and its usual target glutathione-S-transferase. The aforementioned lead molecules can be used to develop novel therapeutic agents towards the protein targets of SARS-CoV-2, and the study provides significant insight for structure-based drug development against COVID-19.

Novel consortia of enterobacter and pseudomonas formulated from cow dung exhibited enhanced biodegradation of polyethylene and polypropylene.

This study prioritizes the biodegradation potential of novel bacterial consortia formulated from cow dung samples towards low-density polyethylene (LDPE) and polypropylene (PP) in comparison with our previous studies. Ten possible consortia were formulated using 10 selected isolates with >10% weight reduction of LDPE and PP, these were pre-treated under UV for 1 h, and their biodegradation potential was studied for 160 days. The isolates present in prioritized consortia were characterized by standard microbiology and 16SrRNA gene sequencing methods. Out of 10 bacterial consortia formulated, potential consortium-CB3 showed greater percentage degradation (weight reduction) of 64.25 ± 2% and 63.00 ± 2% towards LDPE and PP films, respectively (p < 0.05) at 37 °C compared to other consortia. Significant structural variations due to the formation of bacterial biofilm were observed in CB3 treated LDPE and PP films. The three bacteria-IS1, IS2, and IS3-that constituted CB3 were found to be novel strains and designated to be Enterobacter sp nov. bt DSCE01, Enterobacter cloacae nov. bt DSCE02, and Pseudomonas aeruginosa nov. bt DSCE-CD03, respectively. This novel consortium can be scaled up for enhanced degradation of plastic polymers and probably design cost-effective bio-digester for industrial applications using CB3 as potential inoculum.

Deciphering effectual binding potential of xylo-substrates towards xylose isomerase and xylokinase through molecular docking and molecular dynamic simulation.

Xylooligosaccharides (XOS) such as xylobiose and xylotriose are prebiotics with important functions and relevance and the study of interaction mechanism between these substrate and their respective enzymes has scope and applications. Thus, the present study aimed to decipher the interaction mechanisms of xylose isomerase (XylA) and xylokinase (XylB) towards their xylo-substrates namely xylobiose and xylotriose by computational modeling and molecular dynamic simulation studies. The three-dimensional structures of XylA and XylB, not available in their native forms, were predicted, energy minimized and validated by various computational biology tools and software. The binding mechanisms of xylobiose and xylotriose towards XylA and XylB were modeled by molecular docking and the stability of the docked complexes was confirmed by molecular dynamic (MD) simulation. The current study suggested that the theoretical models of XylA and XylB possessed good stereo-chemical validity, structural stabilities and minimum energy conformers. The molecular docking studied showed that xylotriose showed better binding interactions to XylA than xylobiose and xylobiose showed better binding interaction to XylB than xylotriose with ideal root mean square deviation (RMS), minimum binding energy (kcal/mol), hydrogen bonding and weak interactions. The MD simulation confirmed the stabilities of the docked complexes predicted by docking studies. The study suggested that interactions between the probiotics and prebiotics and provides the novel insights in exploring synbiotics as functional foods towards their futuristic applications. [Formula: see text]HighlightsThis study deciphers the interactions of xylosubstrates to XylA and XylB.The XylA and XylB possessed ideal structural stability and stereochemistryXylotriose and Xylobiose showed significant interactionsThe interactions of Xylotriose-XylA and Xylobiose-XylB were found stable in MD studies.Communicated by Ramaswamy H. Sarma.

Carbon fullerene acts as potential lead molecule against prospective molecular targets of biofilm-producing multidrug-resistant Acinetobacter baumanni and Pseudomonas aerugenosa: computational modeling and MD simulation studies.

This study aimed to screen putative drug targets associated with biofilm formation of multidrug-resistant Acinetobacter baumannii and Pseudomonas areugenosa and prioritize carbon nano-fullerene as potential lead molecule by structure-based virtual screening. Based on the functional role, 36 and 83 genes that are involved in biofilm formation of A. baumannii and P. areugenosa respectively were selected and metabolic network was computationally constructed. The genes that lack three-dimensional structures were predicted and validated. Carbon nano-fullerene selected as lead molecule and their drug-likeliness and pharmacokinetics properties were computationally predicted. The binding potential of carbon nano-fullerene toward selected drug targets was modeled and compared with the binding of conventional drugs, doripenem, and polymyxin-B with their usual targets. The stabilities of four best-docked complexes were confirmed by molecular dynamic (MD) simulation. This study suggested that selected genes demonstrated relevant interactions in the constructed metabolic pathways. Carbon fullerene exhibited significant binding abilities to most of the prioritized targets in comparison with the binding of last-resort antibiotics and their usual target. The four best ligand-receptor interactions predicted by molecular docking revealed that stability throughout MD simulation. Notably, carbon fullerene exhibited profound binding with outer membrane protein (OmpA) and ribonuclease-HII (rnhB) of A. baumannii and 2-heptyl-4(1H)-quinolone synthase (pqsBC) and chemotaxis protein (wspA) of P. aeruginosa. Thus, the current study suggested that carbon fullerene was probably used as potential lead molecules toward selected targets of A. baumannii and P. aeruginosa and the applied aspects probably scaled up to design promising lead molecules toward these pathogens. Communicated by Ramaswamy H. Sarma.

C-demethylation and 1, 2-amino shift in (E)-2-(1-(3-aminophenyl) ethylidene)hydrazinecarboxamide to (E)-2-(2-aminobenzylidene)hydrazinecarboxamide and their applications.

A Novel (E)-2-(1-(3-aminophenyl)ethylidene)hydrazinecarboxamide 1 was synthesized by traditional method and converted to (E)-2-(2-aminobenzylidene)hydrazinecarboxamide 2 by single step in DMSO at room temperature. Synthesized compound 1 was analysed by spectroscopy (NMR and LC-MS) techniques and molecule 2 was characterized using single crystal X-ray diffraction and spectroscopy (NMR and GC-MS) techniques. These analytical technique results revealed that, C-demethylation and 1, 2 amino shift in phenyl ring of compound 1 gives molecule 2. DNA binding studies of compounds 1 and 2 was carried out by electronic absorption spectroscopy. This result revealed that, compounds 1 and 2 showed hyperchromism with bathochromic shift. Anticancer activity of compounds 1 and 2 is carried out by molecular docking with five receptors.Computer aided virtual screening demonstrated that the synthesized molecules possess ideal drug likeliness, pharmacokinetics features, toxicity profile for structure based drug discovery. The molecular docking studies revealed that the synthesized molecules are significant binding with the five selected cancer receptors with minimum binding energy (kcal/mol), number of hydrogen bonds, weak interaction, docking score and cluster RMS. The docking studies also suggested that the molecules showed interactions with DNA and the theoretical values of the binding are comparable with that of the experimental values. Hirshfeld surface analysis was used to analyze and quantify the intermolecular interactions in the crystal structure of compound 2.

Structural and molecular basis of the interaction mechanism of selected drugs towards multiple targets of SARS-CoV-2 by molecular docking and dynamic simulation studies- deciphering the scope of repurposed drugs.

The repurposing of FDA approved drugs is presently receiving attention for COVID-19 drug discovery. Previous studies revealed the binding potential of several FDA-approved drugs towards specific targets of SARS-CoV-2; however, limited studies are focused on the structural and molecular basis of interaction of these drugs towards multiple targets of SARS-CoV-2. The present study aimed to predict the binding potential of six FDA drugs towards fifteen protein targets of SARS-CoV-2 and propose the structural and molecular basis of the interaction by molecular docking and dynamic simulation. Based on the literature survey, fifteen potential targets of SARS-CoV-2, and six FDA drugs (Chloroquine, Hydroxychloroquine, Favipiravir, Lopinavir, Remdesivir, and Ritonavir) were selected. The binding potential of individual drug towards the selected targets was predicted by molecular docking in comparison with the binding of the same drugs with their usual targets. The stabilities of the best-docked conformations were confirmed by molecular dynamic simulation and energy calculations. Among the selected drugs, Ritonavir and Lopinavir showed better binding towards the prioritized targets with minimum binding energy (kcal/mol), cluster-RMS, number of interacting residues, and stabilizing forces when compared with the binding of Chloroquine, Favipiravir, and Hydroxychloroquine, later drugs demonstrated better binding when compared to the binding with their usual targets. Remdesvir showed better binding to the prioritized targets in comparison with the binding of Chloroquine, Favipiravir, and Hydroxychloroquine, but showed lesser binding potential when compared to the interaction between Ritonavir and Lopinavir and the prioritized targets. The structural and molecular basis of interactions suggest that the FDA drugs can be repurposed towards multiple targets of SARS-CoV-2, and the present computational models provide insights on the scope of repurposed drugs against COVID-19.

Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies.

Pseudomonas aeruginosa has become a global concern due to its extreme resistance to most of the last resort antibiotics. Present study focuses on the screening of potential molecular targets involved in regulation of biofilm formation in P. aeruginosa and identification of potential natural lead molecules against these targets by molecular modelling, docking and simulation studies. Response regulator (GacA) and transcriptional activator (RhlR) involved in biofilm formation in P. aeruginosa were identified as molecular targets by metabolic pathway analysis and the three dimensional structures of these proteins were predicted by homology modelling and validated. By thorough literature survey, 78 lead molecules were screened and their pharmacokinetic profiles were determined and best two of them selected. The binding potential of selected lead molecules against GacA and RhlR were predicted by molecular docking and their binding energy was compared with the interaction of meropenem and its usual target penicillin binding protein-3. The stabilities of best docked complex were studied by molecular dynamic (MD) simulation. This study showed that Celastrol present in Celastrus paniculatus and Rotiorinol present in Chaetomium cupreum showed better binding affinities with GacA (binding energy -7.2 kcal/mol) and RhlR (binding energy -8.0 kcal/mol) respectively in comparison with the binding of Meropenem and its target (binding energy -6.2 kcal/mol). MD simulation studies showed that GacA-Celastrol and RhlR-Rotiorinol complexes demonstrated conformational stability throughout the simulation. This study highlights the application of GacA and RhlR as prospective targets and Celastrol and Rotiorinol are the potential lead molecules towards biofilm producing drug resistant P. aeruginosa.