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The Schiff-base probe H2VL [6,6'-((1E,1'E)-hydrazine-1,2 diylidenebis(methanylylidene))bis(2-methoxyphenol)] is synthesized and structurally characterized by single crystal X-ray diffraction (SCXRD). H2VL is able to detect selectively acetate ion (OAc-) colorimetrically over other anions with 1:1 co-ordination. The detection limit is found to be 4.93 µM. On the other hand, fluorescence intensity of the receptor is drastically enhanced with Zn2+ and Cd2+ in the presence of acetate as counter anion. N, N-Dimethyl formamide (DMF) or Dimethylsulphoxide (DMSO) and acetate (OAc-) was the best solvent and counter anion for Zn2+/Cd2+ -sensing compared with other solvents and anions, respectively. Detection limit for Zn2+ and Cd2+ are calculated to be 1.94 µM and 1.99 µM, respectively. The strong selective emissive behavior could be attributed to the CHEF (chelation-enhanced fluorescence) process. According to the changes in output emission intensity in DMSO in response to the set of ions (Zn2+, Cd2+ and OAc¯) as input variables, the function of 3-input multifunctional molecular logic circuits has been demonstrated. The molecular docking studies of H2VL with DNA and BSA are also performed to confirm its possible bioactivity. [ABSTRACT FROM AUTHOR]

A terpyridyl-based binuclear Cu(II) complex, formulated as [Cu2(tpy)2(muco)(NO3)2], (1) (typ = 2,2';6',2"-terpyridine and H2-muco = trans, trans-muconic acid) was synthesised in a single pot technique using slow evaporation method. Blue coloured distorted octahedral-shaped crystals were obtained after a day. Synthesised compound has been characterised by elemental analysis as well as single crystal X-ray diffraction (SCXRD) techniques. Hirshfeld surface analysis has been explored to check out the nature of intermolecular interactions and packing modes of compounds in the crystalline state. From the docking study, it has been found that the metal complex bind to the major groove of DNA and the planner aromatic pyridine ring of the ligand partially intercalate into the base pairs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Zinc complex with a N4-donor Schiff base. • Crystal structure. • DFT study. • Pharmacological properties. Abstract A tetradentate Schiff base ligand, L (L = N , N ′-bis(1-(2-pyridyl)ethylidene)-2,2-dimethylpropane-1,3-diamine) was used in the preparation of a new mononuclear Zn(II) complex, [Zn(L)Cl]. The complex was structurally investigated by elemental analyses, spectroscopic studies and single crystal X-ray crystallography. Furthermore, to obtain insights into the structure, the ground state geometry of zinc complex cation was examined by dispersion corrected DFT method i.e. B3LYP-D3 within unrestricted scheme. Intermolecular contacts in the crystal structure were calculated and quantified by examination of Hirshfeld surface and fingerprint plots. In addition, the pharmacological properties of the newly synthesized complex were examined to explore the in vitro antibiofilm activity against P. aeruginosa , and anticancer activity against Human breast adenocarcinoma (MCF-7) cell line. Furthermore, molecular docking study was also recorded to find out various modes of virtual interactions between the zinc complex cation and the active site of receptor (PDB: 1gzt). [ABSTRACT FROM AUTHOR]

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. [Display omitted] • PLpro is encoded within nsp3 is an important drug target for COVID-19 drug therapeutics. • It is evident that food constituents crucial for prevention of coronavirus infection. • Virtually the FooDB database is screened against PLpro protein. • Through multiple pharmacoinformatics approach four molecules found crucial for PLpro inhibition. • Molecular docking and dynamics studies substantiated the potentiality of the molecules. [ABSTRACT FROM AUTHOR]

• Complex between BI-224436 and HIV-1 integrase was used to design novel anti-HIV inhibitors. • The de novo approach available in LigBuilder was used. • A number of criteria was used to narrow down the chemical space of initial designed 80,000 inhibitors. • Different pharmacokinetics parameters were checked for final proposed molecules. • MD simulation was performed of HIV-1 integrase complex with proposed molecules. In the present study, pharmacoinformatics paradigms include receptor-based de novo design, virtual screening through molecular docking and molecular dynamics (MD) simulation are implemented to identify novel and promising HIV-1 integrase inhibitors. The de novo drug/ligand/molecule design is a powerful and effective approach to design a large number of novel and structurally diverse compounds with the required pharmacological profiles. A crystal structure of HIV-1 integrase bound with standard inhibitor BI-224436 is used and a set of 80,000 compounds through the de novo approach in LigBuilder is designed. Initially, a number of criteria including molecular docking, in-silico toxicity and pharmacokinetics profile assessments are implied to reduce the chemical space. Finally, four de novo designed molecules are proposed as potential HIV-1 integrase inhibitors based on comparative analyses. Notably, strong binding interactions have been identified between a few newly identified catalytic amino acid residues and proposed HIV-1 integrase inhibitors. For evaluation of the dynamic stability of the protein-ligand complexes, a number of parameters are explored from the 100 ns MD simulation study. The MD simulation study suggested that proposed molecules efficiently retained their molecular interaction and structural integrity inside the HIV-1 integrase. The binding free energy is calculated through the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach for all complexes and it also explains their thermodynamic stability. Hence, proposed molecules through de novo design might be critical to inhibiting the HIV-1 integrase. [ABSTRACT FROM AUTHOR]

The cyclin-dependent kinase-2 (CDK2) belongs to the protein kinase family and its overexpression leads to an unusual regulation of cell-cycle which directly linked with hyperproliferation in many cancer cell types. CDK2 activation spontaneously promotes the cell cycle progression and also involved in a large number of cellular processes including cell cycle regulation, DNA replication, DNA damage response and apoptotic pathways, therefore targeting the CDK2 can be reemerged as a therapeutic boulevard to restrain cancer cell proliferation. For the last two decades, emerging evidences suggested that CDK2 inhibition draws out some antitumor/anticancer activity, which has driven the research possibility for developing next-generation newer or cost-effective inhibitors with greater specificity to CDK2. In the current work, compounds from the FooDB - a world's largest food constituents database was retrieved and curated and followed by multi-pharmacoinformatics approaches adopted to find out potential CDK2 inhibitors. The curated dataset was considered for screening through "Virtual Screening Workflow" (VSW) employed in Schrödinger suite. The numbers of cost-effective food constituents were reduced by removing low potential molecules in terms of interaction affinity and further explored for pharmacokinetics analysis. Based on strong binding interaction profiles with the lowest binding interactions affinity and energy values, four food compounds were proposed as CDK2 inhibitors. A number of key analyzing parameters from molecular dynamics (MD) simulations studies were successfully substantiated that all four proposed food compounds can act as CDK2 inhibitors based on their proficient structural and molecular interactions integrity with CDK2 protein following in the active site cavity. Furthermore, the binding free energy was calculated using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approach from the entire trajectory frames derived in MD simulation revealed strong interaction affinity. The binding free energy was found to be in the range of −991.831 to −210.452 kJ/mol. High binding free energy was undoubtedly explained that all molecules possess strong affection towards CDK2. Hence, proposed molecules may be crucial to stop the hyperproliferation in cancer cells subjected to experimental validation. • Compounds from FooDB were virtually screened to identify potential CDK2 inhibitors. • Through virtual screening workflow four potential molecules were identified as CDK2 inhibitors. • Different pharmacokinetics parameters were checked for final proposed molecules. • 100 ns MD simulation study was performed for all proposed molecules bound with CDK2. • The binding free energy was calculated using MM-PBSA approach. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder generally developed with aging. AD slowly hammers the memory and cognitive abilities which eventually leads to abnormal behaviour, and ultimately left with disability and dependency. It is anticipated that by the year 2050, world population will experience the incidence of 100 million AD cases. It has been more than hundred years passed since AD recognized as a dreadfull disease, but there is no effective curative agent discovered against AD to date. One of the major hallmarks of the AD development is the accumulation of extracellular amyloid-beta (Aβ) plaques in the brain. In the amyloidogenic process, an extensively studied beta-secretase enzyme, known as BACE1, plays a key role in the accumulation and production of Aβ fragments. Therefore, successful inhibition of BACE1 by small molecular chemical entities can be an effective approach for anti-AD drug development. Hence, the current study has been perceived to find out potential BACE1 inhibitiors by virtual screening of entire Asinex chemical library database through multi-step molecular docking methodologies. Further, sequential screening of in-silico pharmacokinetics, molecular dynamic (MD) simulations analyses along with binding free energy estimation were performed. Comparative analyses and characteristics of molecular binding interactions assessment finally suggests that five molecules (B1–B5) to be the most promising BACE1 inhibitors. Molecular interactions analyses revealed that either one or both the catalytic dyad residues (Asp32 and Asp228) of BACE1 has formed strong molecular interactions with all the proposed molecules. Not only the catalytic dyad residues are involved in the formation of molecular binding interactions but also other important non-Asp binders residues such as Gly34, Tyr71, Trp115, Arg128, Lys224, Gly230, Thr231, Thr232, Arg235, Thr329, and Val332 found to interact with the selected compounds. Moreover, the dynamic behaviour of proposed molecules and BACE1 was explored through all-atoms MD simulation study for 100 ns time span. Analysis of MD simulation trajectories explained that all identified molecules are efficient enough to retain the structural and molecular interactions integrity inside the receptor cavity of BACE1 in dynamic environment. Finally, the binding free energy of each molecule has calculated from MD simulation trajectories through MM-PBSA method and found that all molecules possess a strong binding affinity towards the BACE1. The high negative binding free energies are found to be within the range of −994.978 to −561.562 kJ/mol for the identified compounds. Henceforth, analyses of extensively studied multi-cheminformatics approaches explained that proposed molecules might be promising BACE1 inhibitors for therapeutic application in AD, subjected to experimental validation. Image 1 • CNS-Asinex database was virtually screened to identify potential BACE1 inhibitors. • Through docking and VSW five potential molecules were identified as BACE1 inhibitors. • Different pharmacokinetics parameters were checked for final proposed molecules. • MD simulation was performed of BACE1 complex with proposed molecules. • The binding energy was calculated using MM-PBSA approach. [ABSTRACT FROM AUTHOR]

• Wild type Catalase-peroxidase enzyme (WT katG) mutated into five mutant katG (MT katG). • Molecular docking was performed WT and MT katG. • Screening was performed based on binding energy of Isoniazid and promising katG inhibitors proposed. • MD simulation was performed for MT katG-proposed molecules complex. • Binding energy of proposed molecules was calculated using MM-PBSA approach. Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). In the present age, due to the rapid increase in antibiotic resistance worldwide, TB has become a major threat to human life. Regardless of significant efforts have been inclined to improve the healthcare systems for improving diagnosis, treatment, and anticipatory measures controlling TB is challenging. To date, there are no such therapeutic chemical agents available to fight or control the bacterial drug-resistance. The catalase-peroxidase enzyme (katG) which encoded by the katG gene of Mtb is most frequently getting mutated and hence promotes Isoniazid resistance by diminishing the normal activity of katG enzyme. In the current study, an effort has been intended to find novel and therapeutically active antibacterial chemical compounds through pharmacoinformatics methodologies. Initially, the five mutant katG were generated by making mutation of Ser315 by Thr, Ile, Arg, Asn, and Gly followed by structural optimizations. About eight thousand small molecules were collected from the Asinex antibacterial library. All molecules were docked to active site of five mutant katG and wild type katG. To narrow down the chemical space several criteria were imposed including, screening for highest binding affinity towards katG proteins, compounds satisfying various criterion of drug-likeliness properties like Lipinski's rule of five (RO5), Veber's rule, absorption, distribution, metabolism, and excretion (ADME) profile, and synthetic accessibility. Finally, five molecules were found to be important antibacterial katG inhibitors. All the analyzed parameters suggested that selected molecules are promising in nature. Binding interactions analysis revealed that proposed molecules are efficient enough to form a number of strong binding interactions with katG proteins. Dynamic behavior of the proposed molecules with katG protein was evaluated through 100 ns molecular dynamics (MD) simulation study. Parameters calculated from the MD simulation trajectories adjudged that all molecules can form stable complexes with katG. High binding free energy of all proposed molecules definitely suggested strong affection towards the katG. Hence, it can be concluded that proposed molecules might be used as antibacterial chemical component subjected to experimental validation. [ABSTRACT FROM AUTHOR]