Synthesis of the chromone-thiosemicarbazone scaffold as promising α-glucosidase inhibitors: An in vitro and in silico approach toward antidiabetic drug design.

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 µM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 µM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.

Binding selectivity analysis of AURKs inhibitors through molecular dynamics simulation studies.

Aurora kinases (AURKs) have been identified as promising biological targets for the treatment of cancer. In this study, molecular dynamics simulations were employed to investigate the binding selectivity of three inhibitors (HPM, MPY, and VX6) towards AURKA and AURKB by predicting their binding free energies. The results show that the inhibitors HPM, MPY, and VX6 have more favorable interactions with AURKB as compared to AURKA. The binding energy decomposition analysis revealed that four common residue pairs (L139, L83), (V147, V91), (L210, L154), and (L263, L207) showed significant binding energies with HPM, MPY, and VX6, hence responsible for the binding selectivity of AURKA and AURKB to the inhibitors. The MD trajectory analysis also revealed that the inhibitors affect the dynamic flexibility of protein structure, which is also responsible for the partial selectivity of HPM, MPY, and VX6 towards AURKA and AURKB. As expected, this study provides useful insights for the design of potential inhibitors with high selectivity for AURKA and AURKB.

Synthesis, biological evaluation, and molecular docking study of chromen-linked hydrazine carbothioamides as potent α-glucosidase inhibitors.

Inhibiting α-glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Several novel chromen-linked hydrazine carbothioamide (3a-r) were designed and synthesized by condensation of chromone-3-carbaldehyde with a variety of substituted thiosemicarbazides. The structures of these new analogues were elucidated through various advanced spectroscopic techniques (1 H NMR, 13 C NMR, and ESI-MS). The resulted compounds were screened for α-glucosidase inhibitory potential and all the compounds (3a-r) exhibited potent inhibition of α-glucosidase with IC50 values ranging 0.29-53.70 µM. Among them compounds 3c, 3f, 3h, and 3r displayed the highest α-glucosidase inhibitor capability with IC50 values of 1.50, 1.28, 1.08, and 0.29 µM, respectively. Structure-activity relationship showed that different substituted groups are responsible for the variation in the α-glucosidase inhibition. The kinetics studies of the most active inhibitor (3r) were performed, to investigate the mode of inhibition and dissociation constants (Ki), that indicated a competitive inhibitor with Ki value of 1.47 ± 0.31 µM. Furthermore, molecular docking studies was performed to reveal the possible interactions, such as H-bonding, or π-π stacking, with the key residues of α-glucosidase. Docking analysis revealed the importance of hydrazine carbothioamide moiety of compounds in the attachment of ligands with the crucial residues of α-glucosidase. The estimated pharmacokinetic, physicochemical, and drug likeness properties of compounds 3a-r reflects that these molecules have acceptable range of these properties.

Synthesis of novel 3-hydroxy-2-naphthoic hydrazones as selective chemosensors for cyanide ions.

The development of an effective and selective chemosensor for CN- ions has become the need of the hour due to their hazardous impact on the environment and humans. Herein, we report the synthesis of two novel chemosensors, IF-1 and IF-2 based on 3-hydroxy-2-naphthohydrazide and aldehyde derivatives that have shown selective sensing of CN- ions. IF-2 exhibited exclusive binding with CN- ions that is further confirmed by the binding constant value of 4.77 × 104 M-1 with a low detection limit (8.2 µM). The chemosensory potential is attributed to deprotonation of the labile Schiff base center by CN- ions that results in a color change from colorless to yellow as visible by the naked eye. Accompanying this, a DFT study was also performed in order to find the interaction between the sensor (IF-1) and its ions (F-). A notable charge transfer from 3-hydroxy-2-naphthamide to 2,4-di-tert-butyl-6-methylphenol, was indicated by the FMO analysis. The QTAIM analysis revealed that in the complex compound, the strongest pure hydrogen-hydrogen bonding was observed between H53 and H58, indicated by a ρ value of +0.017807. Due to its selective response, IF-2 can be successfully used for making test strips for the detection of CN- ions.

Identification of human phosphoglycerate mutase 1 (PGAM1) inhibitors using hybrid virtual screening approaches.

PGAM1 plays a critical role in cancer cell metabolism through glycolysis and different biosynthesis pathways to promote cancer. It is generally known as a crucial target for treating pancreatic ductal adenocarcinoma, the deadliest known malignancy worldwide. In recent years different studies have been reported that strived to find inhibitory agents to target PGAM1, however, no validated inhibitor has been reported so far, and only a small number of different inhibitors have been reported with limited potency at the molecular level. Our in silico studies aimed to identify potential new PGAM1 inhibitors that could bind at the allosteric sites. At first, shape and feature-based models were generated and optimized by performing receiver operating characteristic (ROC) based enrichment studies. The best query model was then employed for performing shape, color, and electrostatics complementarity-based virtual screening of the ChemDiv database. The top two hundred and thirteen hits with greater than 1.2 TanimotoCombo score were selected and then subjected to structure-based molecular docking studies. The hits yielded better docking scores than reported compounds, were selected for subsequent structural similarity-based clustering analysis to select the best hits from each cluster. Molecular dynamics simulations and binding free energy calculations were performed to validate their plausible binding modes and their binding affinities with the PGAM1 enzyme. The results showed that these compounds were binding in the reported allosteric site of the enzyme and can serve as a good starting point to design better active selective scaffolds against PGAM1enzyme.

Design, Synthesis, and Density Functional Theory Studies of Indole Hydrazones as Colorimetric "Naked Eye" Sensors for F Ions.

A new series of sensors SM-1 to SM-3 was designed and synthesized using indole carboxaldehydes (2a-2c) and 2,4-dinitrophenyl hydrazine. Accompanied by the synthesis, density functional theory investigation was also accomplished at the M06-2X/6-311G+(d,p) functional. A reduction in band gap (ΔE = 4.702-4.230 eV) along with a bathochromic shift (λmax = 433.223-471.584 nm) was seen in deprotonated chromophores than their neutral sensors. Further, significant charge transference from indole toward dinitrophenyl hydrazine was also examined. Global reactivity parameters also expressed the greater stability of sensors than that of their deprotonated form. SM-3 displayed high selectivity toward F ions as compared to SM-1 and SM-2, which respond to both F- and CN- ions. The electronic absorption spectrum was recorded in CH3CN. The sensor SM-3 showed high selectivity toward F- ions with a low detection limit (8.69 × 10-8), and the binding constant for SM-3 was determined as 7.7 × 105. The sensor displayed naked eye views as the color of solution changed from mustard to purple with a red shift of 96 nm. The mechanism suggests deprotonation from the NH group, which was confirmed by 1H NMR. The sensor is found to be useful for detection of F- ions in the real sample and for analytical application (test strip).

Pyrazole derivatives of pyridine and naphthyridine as proapoptotic agents in cervical and breast cancer cells.

Cancer is one of the leading causes of death worldwide. The increasing prevalence and resistance to chemotherapy is responsible for driving the search of novel molecules to combat this disease. In search of novel compounds with pro-apoptotic potential, pyrazolo-pyridine and pyrazolo-naphthyridine derivatives were investigated against cervical cancer (HeLa) and breast cancer (MCF-7) cells. The anti-proliferative activity was determined through the MTT assay. Potent compounds were then analyzed for their cytotoxic and apoptotic activity through a lactate dehydrogenase assay and fluorescence microscopy after propidium iodide and DAPI staining. Flow cytometry was used to determine cell cycle arrest in treated cells and pro-apoptotic effect was verified through measurement of mitochondrial membrane potential and activation of caspases. Compounds 5j and 5k were found to be most active against HeLa and MCF-7 cells, respectively. G0/G1 cell cycle arrest was observed in treated cancer cells. Morphological features of apoptosis were also confirmed, and an increased oxidative stress indicated the involvement of reactive oxygen species in apoptosis. The compound-DNA interaction studies demonstrated an intercalative mode of binding and the comet assay confirmed the DNA damaging effects. Finally, potent compounds demonstrated a decrease in mitochondrial membrane potential and increased levels of activated caspase-9 and -3/7 confirmed the induction of apoptosis in treated HeLa and MCF-7 cells. The present work concludes that the active compounds 5j and 5k may be used as lead candidates for the development of lead drug molecules against cervical and breast cancer.

Synthesis, Biological Evaluation, and Molecular Dynamics of Carbothioamides Derivatives as Carbonic Anhydrase II and 15-Lipoxygenase Inhibitors.

A series of hydrazine-1-carbothioamides derivatives (3a-3j) were synthesized and analyzed for inhibitory potential towards bovine carbonic anhydrase II (b-CA II) and 15-lipoxygenase (15-LOX). Interestingly, four derivatives, 3b, 3d, 3g, and 3j, were found to be selective inhibitors of CA II, while other derivatives exhibited CA II and 15-LOX inhibition. In silico studies of the most potent inhibitors of both b-CA II and 15-LOX were carried out to find the possible binding mode of compounds in their active site. Furthermore, MD simulation results confirmed that these ligands are stably bound to the two targets, while the binding energy further confirmed the inhibitory effects of the 3h compound. As these compounds may have a role in particular diseases, the reported compounds are of great relevance for future applications in the field of medicinal chemistry.

1,3,5-Thiadiazinane thione derivatives as significant urease inhibitors.

We report the promising urease inhibitory activity of four sets of tetrahydro thiadiazine thiones (THTT) namely 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine thiones: THTT 5-8 (set A) having alkyl/aryl substituents at N-3 and N-5 positions; THTT 9-12 (set B) and THTT 13-14 (set C) with 3-carboxylic acid derivatives and tetrahydro-2H-1,3,5-thiadiazine-6-thione esters 15-16 (set D). Gratifyingly, all four sets of THTT were recognized as promising inhibitors of urease enzyme. Among 12 tested compounds; THTT 6, 8, 10, 14 and 15 from each set respectively, demonstrated significant urease inhibitory activity with IC50 values between 11.2-29.8µM which is mostly found higher than that for thiourea, a standard urease inhibitor with IC50 value of 22.4µM. Furthermore, compound 7 showed almost the same level of inhibition (IC50 = 22.5µM) as of standard. In addition, molecular docking study supported the phenomenon that thiadiazinane ring itself is an active pharmacophore that binds through CH2 groups and S atom via carbon-hydrogen/π-sulfur interactions respectively to the active site of the urease enzyme. The optimistic results from this study suggest the use of thiadiazinane skeleton as a guided template for the advancement of new urease inhibitors in drug discovery.

Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study.

The role of aldose reductase (ALR2) in causing diabetic complications is well-studied, with overactivity of ALR2 in the hyperglycemic state leading to an accumulation of intracellular sorbitol, depletion of cytoplasmic NADPH and oxidative stress and causing a variety of different conditions including retinopathy, nephropathy, neuropathy and cardiovascular disorders. While previous efforts have sought to develop inhibitors of this enzyme in order to combat diabetic complications, non-selective inhibition of both ALR2 and the homologous enzyme aldehyde reductase (ALR1) has led to poor toxicity profiles, with no drugs targeting ALR2 currently approved for therapeutic use in the Western world. In the current study, we have synthesized a series of N-substituted thiosemicarbazones with added phenolic moieties, of which compound 3m displayed strong and selective ALR2 inhibitory activity in vitro (IC50 1.18 µM) as well as promising antioxidant activity (75.95% free radical scavenging activity). The target binding modes of 3m were studied via molecular docking studies and stable interactions with ALR2 were inferred through molecular dynamics simulations. We thus report the N-substituted thiosemicarbazones as promising drug candidates for selective inhibition of ALR2 and possible treatment of diabetic complications.

Nucleotide pyrophosphatase/phosphodiesterases (NPPs) including NPP1 and NPP2/ ATX as important drug targets: A patent review (2015-2020).

INTRODUCTION: Ectobucleotidases are a broad class of extracellular nucleotide and nucleoside hydrolyzing enzymes. Since they play a crucial role in mediating purinergic cell signalling, they are promising therapeutic targets for treatment of a range of disorders, including fibrosis, tumor metastasis, inflammation, multiple sclerosis, and autoimmune diseases. Hence selective inhibtors of ectonulceotidases are of great interest for therapeutic intervention. AREA COVERED: Many compounds have demonstrated promising inhibitory potential against ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs). The chemistry and clinical applications of NPP inhibitors patented between 2015 and 2020 are discussed in this review. EXPERT OPINION: In recent years, there has been a lot of effort towards finding effective and selective inhibitors of NPPs. Even though a number of inhibitors are known, only a few in vivo investigations have been published. In addition to IOA-289, which has passed Phase Ia clinical trials, potent NPP2/ATX inhibitor compounds such as BLD-0409, IPF and BBT-877 have been placed in phase I clinical studies. Some of the most promising NPP2/ATX inhibitors in recent years are closely related analogs of previously known inhibitors, such as PF-8380. Knowledge of the structure activity relationship of such promising inhibitors can potentially translate into the discovery of more potent and effective inhibitors of NPP.

Folate Conjugated Polyethylene Glycol Probe for Tumor-Targeted Drug Delivery of 5-Fluorouracil.

A targeted delivery system is primarily intended to carry a potent anticancer drug to specific tumor sites within the bodily tissues. In the present study, a carrier system has been designed using folic acid (FA), bis-amine polyethylene glycol (PEG), and an anticancer drug, 5-fluorouracil (5-FU). FA and PEG were joined via an amide bond, and the resulting FA-PEG-NH2 was coupled to 5-FU producing folate-polyethylene glycol conjugated 5-fluorouracil (FA-PEG-5-FU). Spectroscopic techniques (UV-Vis, 1HNMR, FTIR, and HPLC) were used for the characterization of products. Prodrug (FA-PEG-5-FU) was analyzed for drug release profile (in vitro) up to 10 days and compared to a standard anticancer drug (5-FU). Folate conjugate was also analyzed to study its folate receptors (FR) mediated transport and in vitro cytotoxicity assays using HeLa cancer cells/Vero cells, respectively, and antitumor activity in tumor-bearing mice models. Folate conjugate showed steady drug release patterns and improved uptake in the HeLa cancer cells than Vero cells. Folate conjugate treated mice group showed smaller tumor volumes; specifically after the 15th day post-treatment, tumor sizes were decreased significantly compared to the standard drug group (5-FU). Molecular docking findings demonstrated importance of Trp138, Trp140, and Lys136 in the stabilization of flexible loop flanking the active site. The folic acid conjugated probe has shown the potential of targeted drug delivery and sustained release of anticancer drug to tumor lesions with intact antitumor efficacy.

Synthesis and Characterization of Imidazolium-Based Ionic Liquids and Evaluating Their Performance as Asphaltene Dispersants.

With the projected increase in the production of heavy oil due to the energy crisis, asphaltene-related issues are likely to come to the forefront. This leads to operational problems, safety hazards, and oil production deficiencies, resulting in huge economic losses for the petroleum industry. Therefore, in this work, we aimed to inhibit asphaltene precipitation using ionic liquid (IL) compounds. ILs with long alkyl chains can inhibit the precipitation of asphaltene molecules due to the π-π* interactions between them and the formation of hydrogen bonds. A series of imidazolium-based ionic liquids, IL-0, IL-4, IL-10, and IL-16, were synthesized with yield percents of 79, 81, 80, and 83%, respectively. The prepared materials were characterized well using FTIR, 1H-NMR, and Elemental Analysis. The surface tension, interfacial tension (IFT), and different surface parameters were investigated at different temperatures to simulate the reservoir temperature. IL-0, IL-4, IL-10, and IL-16 displayed their γcmc values at 35, 34, 31, and 32 mN/m at 303 °K, respectively. It was found that the prepared ILs are good surfactants with low values of interfacial tension. Quantum structure-activity relationships using Density Functional Theory (DFT) were used to investigate the geometry optimization electronic structures, the energy gap (ΔE), and the reactivity of the cations of the prepared ILs. The synthesized ILs were evaluated as asphaltene dispersants using two different techniques. The viscometric technique showed that the asphaltene onset precipitation was 28.5 vol.%. This percent was postponed to 42.8, 50, 78.5, and 64.3 vol.%, after adding IL-0, IL-4, IL-10, and IL-16, respectively, and the spectroscopic technique confirmed the results.

Fabrication and Characterization of Polypyrrole/Multi-Walled Carbon Nanotubes Thin Films Using Thermal Evaporation.

Polypyrrole/multiwalled carbon nanotubes composites (PPy/MWCNTs) were produced in an acidic solution utilizing an in situ oxidative polymerization method using ferric chloride as an oxidizing agent and sodium dodecyl sulfate as a soft template. Thermal evaporation was used to fabricate thin films from polypyrrole/multiwalled carbon nanotube composites. The resulting composites were examined by different techniques to explore their morphology, structural and electrical characteristics. The surface morphology analysis revealed that polypyrrole structure is a two-dimensional film with impeded nanoparticles and the thickness of coated PPy around the MWCNTs decreases when increasing the amount of MWCNTs. XRD analysis revealed that the average crystallite size of the prepared composites is 62.26 nm. The direct energy gap for PPy is affected by a factor ranging from 2.41 eV to 1.47 eV depending on the contents of MWCNTs. The thin film's optical properties were examined using experimental and TDDFT-DFT/DMOl3 simulation techniques. The optical constants and optical conductivity of the composites were calculated and correlated. The structural and optical characteristics of the simulated nanocomposites as single isolated molecules accord well with the experimental results. The nanocomposite thin films demonstrated promising results, making them a viable candidate for polymer solar cell demands. Under optimal circumstances, the constructed planar heterojunction solar cells with a 75 ± 3 nm layer of PPy/MWCNTs had a power conversion efficiency (PCE) of 6.86%.

Synthesis, characterization and biological evaluation of indomethacin derived thioureas as purinergic (P2Y1, P2Y2, P2Y4, and P2Y6) receptor antagonists.

G-protein-coupled receptors for extracellular nucleotides are known as P2Y receptors and are made up of eight members that are encoded by distinct genes and can be classified into two classes based on their affinity for specific G-proteins. P2Y receptor modulators have been studied extensively, but only a few small-molecule P2Y receptor antagonists have been discovered so far and approved by drug agencies. Derivatives of indole carboxamide have been identified as P2Y12 and P2X7 antagonist, as a result, we developed and tested a series of indole derivatives4a-lhaving thiourea moiety as P2Y receptor antagonist by using a fluorescence-based assay to measure the inhibition of intracellular calcium release in 1321N1 astrocytoma cells that had been stably transfected with the P2Y1, P2Y2, P2Y4 and P2Y6 receptors. Most of the compounds exhibited moderate to excellent inhibition activity against P2Y1 receptor subtype. The series most potent compound, 4h exhibited an IC50 value of 0.36 ± 0.01 µM selectivity against other subtypes of P2Y receptor. To investigate the ligand-receptor interactions, the molecular docking studies were carried out. Compound 4h is the most potent P2Y1 receptor antagonist due to interaction with an important amino acid residue Pro105, in addition to Ile108, Phe119, and Leu102.

A Novel Trace-Level Ammonia Gas Sensing Based on Flexible PAni-CoFe2O4 Nanocomposite Film at Room Temperature.

In this study, we developed a new chemi-resistive, flexible and selective ammonia (NH3) gas sensor. The sensor was prepared by depositing thin film of polyaniline-cobalt ferrite (PAni-CoFe2O4) nanocomposite on flexible polyethylene terephthalate (PET) through an in situ chemical oxidative polymerization method. The prepared PAni-CoFe2O4 nanocomposite and flexible PET-PAni-CoFe2O4 sensor were evaluated for their thermal stability, surface morphology and materials composition. The response to NH3 gas of the developed sensor was examined thoroughly in the range of 1-50 ppm at room temperature. The sensor with 50 wt% CoFe2O4 NPs content showed an optimum selectivity to NH3 molecules, with a 118.3% response towards 50 ppm in 24.3 s response time. Furthermore, the sensor showed good reproducibility, ultra-low detection limit (25 ppb) and excellent flexibility. In addition, the relative humidity effect on the sensor performance was investigated. Consequently, the flexible PET-PAni-CoFe2O4 sensor is a promising candidate for trace-level on-site sensing of NH3 in wearable electronic or portable devices.

Toxic and heavy metals contamination assessment in soil and water to evaluate human health risk.

Due to urbanization and industrialization, there has been an increase in solid waste generation and has become a global concern and leakage of leachate from landfills contaminate the soil and groundwater and hence can have a severe impact on human health. The present study aimed to determine the composition of toxic metals (Cr, Mn, Cu, As) and heavy metals (Cd, Ba, Hg, Pb) in soil and water by an inductively coupled plasma optical emission spectrometer (ICP-OES). To ensure accuracy during the analysis of Cr, Mn, Cu, As, Cd, Ba, Hg, and Pb in real samples, certified reference material (CRM, SRM 2709a) of San Joaquin soil and water (SRM 1640a) were analyzed and results were presented in terms of % recovery studies. The mean concentration of all the metals in soil and water did not exceed the limit set by the European Community (EU), WHO, and US EPA except Cu where the permissible limit defined by the EU is 50-140 mg/kg in soil. The soil is uncontaminated to moderately contaminated with respect to all metals except the Cu and Pb. Among the average daily dose (ADD) of soil, ADDing and ADDinh for children had the maximum dose for all metals than adults while ADDderm was higher in adults. Hazard quotient (HQ) trend in both adults and children was found in order HQing > HQderm > HQinh of soil for all metals except Ba which followed HQing > HQinh > HQderm. Hazard index (HI) values of soil for Cr and Pb in children were 7 and 7.5 times higher than adults respectively. Lifetime cancer risk (LCR) value for Cr by different exposure pathways of soil was 5.361 × 10-4 for children which are at the lower borderline of risk for cancer.

Development of coumarin-thiosemicarbazone hybrids as aldose reductase inhibitors: Biological assays, molecular docking, simulation studies and ADME evaluation.

The over expression of aldose reductase (ALR2) in the state of hyperglycemia causes the conversion of glucose into sorbitol and initiates polyol pathway. Accumulation of sorbitol in insulin insensitive tissue like peripheral nerves, glomerulus and eyes, induces diabetic complications like neuropathy, nephropathy and retinopathy. For the treatment of diabetic complications, the inhibition of aldose reductase (ALR2) is a promising approach. A series of coumarin-based thiosemicarbazone derivatives was synthesized as potential inhibitor of aldose reductase. Compound N-(2-fluorophenyl)-2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)hydrazinecarbiothioamide (3n) was found to be the most promising inhibitor of ALR2 with an IC50 in micromolar range (2.07 µM) and high selectivity, relative to ALR1. The crystal structure of ALR2 complexed with 3n explored the types of interaction pattern which further demonstrated its high affinity. Compound 3n has excellent lead-likeness, underlined by its physicochemical parameters, and can be considered as a likely prospect for further structural optimization to get a drugable molecule.

Acridine-based (thio)semicarbazones and hydrazones: Synthesis, in vitro urease inhibition, molecular docking and in-silico ADME evaluation.

Urease is a bacterial enzyme that is responsible for virulence of various pathogenic bacteria such as Staphylococcus aureus, Proteus mirabilis, Klebsiella pneumoniae, Ureaplasma urealyticum, Helicobacter pylori and Mycobacterium tuberculosis. Increased urease activity aids in survival and colonization of pathogenic bacteria causing several disorders especially gastric ulceration. Hence, urease inhibitors are used for treatment of such diseases. In search of new molecules with better urease inhibitory activity, herein we report a series of acridine derived (thio)semicarbazones (4a-4e, 6a-6l) that were found to be active against urease enzyme. Molecular docking studies were carried out to better comprehend the preferential mode of binding of these compounds against urease enzyme. Docking against urease from pathogenic bacterium S. pasteurii was also carried out with favorable results. In silico ADME evaluation was done to determine drug likeness of synthesized compounds.

Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches.

The bromodomain containing protein 4 (BRD4) recognizes acetylated histone proteins and plays numerous roles in the progression of a wide range of cancers, due to which it is under intense investigation as a novel anti-cancer drug target. In the present study, we performed three-dimensional quantitative structure activity relationship (3D-QSAR) molecular modeling on a series of 60 inhibitors of BRD4 protein using ligand- and structure-based alignment and different partial charges assignment methods by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The developed models were validated using various statistical methods, including non-cross validated correlation coefficient (r²), leave-one-out (LOO) cross validated correlation coefficient (q²), bootstrapping, and Fisher's randomization test. The highly reliable and predictive CoMFA (q² = 0.569, r² = 0.979) and CoMSIA (q² = 0.500, r² = 0.982) models were obtained from a structure-based 3D-QSAR approach using Merck molecular force field (MMFF94). The best models demonstrate that electrostatic and steric fields play an important role in the biological activities of these compounds. Hence, based on the contour maps information, new compounds were designed, and their binding modes were elucidated in BRD4 protein's active site. Further, the activities and physicochemical properties of the designed molecules were also predicted using the best 3D-QSAR models. We believe that predicted models will help us to understand the structural requirements of BRD4 protein inhibitors that belong to quinolinone and quinazolinone classes for the designing of better active compounds.