Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants.

INTRODUCTION: Asthma complications and adverse effects associated with steroidal therapy highlight the need for non-steroidal compounds intercepting asthmatic pathophysiology at multiple targets. The present investigation was carried out to evaluate the tracheal smooth muscle relaxant effect of virtually designed, combinatorially synthesized polyfunctional N-heteroarylamides. METHODS: Virtual screening and molecular docking studies of designed compounds were performed using PyRx and AUTODOCK 4.2 software against molecular targets viz. FLAP, LTB4, and H1 receptor. Cross-validation of virtual screening results and active site, confirmation was performedusingVlife MDS software version 3.5. The combinatorial approach was used to synthesize designed compounds in which heterocyclic amines were reacted with substituted aromatic acid chlorides by nucleophilic substitution reaction to obtain a 5x5 mini-library. The structures of synthesized leads were confirmed by infrared and proton magnetic resonance spectroscopic analysis. Synthesized compounds were evaluated for their smooth muscle relaxation effect on isolated goat tracheal smooth muscle. RESULTS: Results were calculated as a percent decrease in contraction response observed using histamine and LTB4. The tested compounds produced anticipated tracheal smooth muscle relaxant activity. Based on the results of screening the structure-activity relationships (SAR) have been reported. CONCLUSION: Present study concluded that synthesized polyfunctional N-heteroarylamides have a tracheal smooth muscle relaxant effect. The mode of action is predicted from the analysis of virtual screening results. A good correlation was observed between virtual screenings and biological activities of lead molecules suggesting the rationale used to optimize the structural requirements of a ligand for selected targets is appropriate.

In silico evaluation of NO donor heterocyclic vasodilators as SARS-CoV-2 Mpro protein inhibitor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19 disease has been exponentially increasing throughout the world. The mortality rate is increasing gradually as effective treatment is unavailable to date. In silico based screening for novel testable hypotheses on SARS-CoV-2 Mpro protein to discover the potential lead drug candidate is an emerging area along with the discovery of a vaccine. Administration of NO-releasing agents, NO inducers or the NO gas itself may be useful as therapeutics in the treatment of SARS-CoV-2. In the present study, a 3D structure of SARS-CoV-2 Mpro protein was used for the rational setting of inhibitors to the binding pocket of enzyme which proposed that phenyl furoxan derivative gets efficiently dock in the target pocket. Molecular docking and molecular dynamics simulations helped to investigate possible effective inhibitor candidates bound to SARS-CoV-2 Mpro substrate binding pocket. Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations revealed energetic contributions of active site residues of Mpro in binding with most stable proposed NO donor heterocyclic vasodilator inhibitor molecules. Furthermore, principal component analysis (PCA) showed that the NO donor heterocyclic inhibitor molecules 14, 16, 18 and 19 was strongly bound to catalytic core of SARS-CoV-2 Mpro protein, limiting its movement to form stable complex as like control. Thus, overall in silico investigations revealed that 5-oxopiperazine-2-carboxylic acid coupled furoxan derivatives was found to be key pharmacophore in drug design for the treatment of SARS-CoV-2, a global pandemic disease with a dual mechanism of action as NO donor and a worthwhile ligand to act as SARS-CoV-2 Mpro protein inhibitor.Communicated by Ramaswamy H. Sarma.

Discovery of pyridoindole derivatives as potential inhibitors for phosphodiesterase 5A: in silico and in vivo studies.

The aim of this work was to synthesise derivatives from identified plant based pyridoindole lead scaffold, and to assess phosphodiesterase 5A inhibitory potential by in silico and in vivo. Pyridoindole derivatives were synthesised by using six-stage reactor. In silico screening was carried out by grip-based docking methodology. In step-I, tryptophan as a starting material was reacted with different aldehydes and ketones to obtain 11 molecules. In step-II, obtained molecules were reacted with ethanol and benzyl alcohols to obtain D1 to D22 derivatives. In silico investigation resulted in best three molecules D12, D4 and D8 with promising BE score. Oral acute toxicity study of selected molecules resulted in LD50 value 500 mg/kg in rats. The result of in vivo antihypertensive study shown that molecule D12 was found to be the best antihypertensive lead molecule. This study could be a best platform to tailor novel biomolecules for inhibiting phosphodiesterase 5A enzyme in hypertension management.

Computer Assisted Models for Blood Brain Barrier Permeation of 1, 5-Benzodiazepines.

AIM: To generate and validate predictive models for blood-brain permeation (BBB) of CNS molecules using the QSPR approach. BACKGROUND: Prediction of molecules crossing BBB remains a challenge in drug delivery. Predictive models are designed for the evaluation of a set of preclinical drugs which may serve as alternatives for determining BBB permeation by experimentation. OBJECTIVE: The objective of the present study was to generate QSPR models for the permeation of CNS molecules across BBB and its validation using existing in-house leads. METHODS: The present study envisaged the determination of the set of molecular descriptors which are considered significant correlative factors for BBB permeation property. Quantitative Structure- Property Relationship (QSPR) approach was followed to describe the correlation between identified descriptors for 45 molecules and highest, moderate and least BBB permeation data. The molecular descriptors were selected based on drug-likeness, hydrophilicity, hydrophobicity, polar surface area, etc. of molecules that served the highest correlation with BBB permeation. The experimental data in terms of log BB were collected from available literature, subjected to 2D-QSPR model generation using a regression analysis method like Multiple Linear Regression (MLR). RESULTS: The best QSPR model was Model 3, which exhibited regression coefficient as R2= 0.89, F = 36; Q2= 0.7805 and properties such as polar surface area, hydrophobic hydrophilic distance, electronegativity, etc., which were considered key parameters in the determination of the BBB permeability. The developed QSPR models were validated with in-house 1,5-benzodiazepines molecules and correlation studies were conducted between experimental and predicted BBB permeability. CONCLUSION: The QSPR model 3 showed predictive results that were in good agreements with experimental results for blood-brain permeation. Thus, this model was found to be satisfactory in achieving a good correlation between selected descriptors and BBB permeation for benzodiazepines and tricyclic compounds.

Development of lipoprotein-drug conjugates for targeted drug delivery.

Tumour targeting approaches used in cancer chemotherapy offers prolonged, localized, and protected drug interaction with the diseased tissue with minimal side effects and systemic toxicity, which are accountable for the failure of chemotherapy using conventional delivery systems. The purpose of the present study is to develop an anticancer targeted drug delivery system using synthesized lipoproteins with the integration of quality by design approach. Lipoprotein structures were designed, and quality by design approach was implemented to select variables for optimization. Further, the lipoproteins were synthesized and characterized by physicochemical properties. Physical composites of synthesized lipoproteins with the drug (tablets) were prepared and evaluated for post-compression parameters. Moreover, drug-lipoprotein chemical conjugates were synthesized and characterized for physicochemical properties, including cellular drug uptake and cytotoxicity study on HaCaT cancer cells. Synthesized lipoproteins showed good swelling capacity but poor flowability. Nuclear magnetic resonance and infrared spectroscopy of conjugates showed characteristic peaks. Tablets from all batches extended the drug release up to 12 h. All synthesized conjugates showed improved cellular drug uptake (up to 86.1%) and inhibition (87.39%) of HaCat cancer cells. These findings explored the possible use of synthesized lipoproteins in the development of anti-cancer drug formulation against HaCat cancer cells.Communicated by Ramaswamy H. Sarma.

Identification and Investigation of Chalcone Derivatives as Calcium Channel Blockers: Pharmacophore Modeling, Docking Studies, In vitro Screening, and 3D-QSAR Analysis.

BACKGROUND: The chalcones were reported to have many biological activities by showing affinity towards many enzymatic targets. The effect of nitric oxide (NO) on calcium channel was extensively studied in different animals; the study was also carried out for NO donor drug and its effect on calcium channel. Till date, the inhibition of calcium channel is of prime importance in the medicinal chemistry to discover newer vascular smooth muscle relaxant drugs. OBJECTIVE: The main objective of this work is to carry out in silico and in vitro evaluation of NO donor chalcones for calcium channel blocking potency. METHODS: The present work includes in silico evaluation of chalcone derivatives for calcium channel blocking potency. The promising scaffolds were identified after pharmacophore modeling and docking study. The in vitro screening of 21 lead molecules for calcium channel blocking potency was carried out on pulmonary veins of adult goat, IC50 values were determined and 3D QSAR was performed. RESULTS: The pharmacophore modeling revealed that hydrogen bond donor, hydrogen bond acceptor, and hydrophobic groups are important features for calcium channel blocking activity. The docking study revealed the existence of hydrophobic, hydrogen bond and Vander wall's interactions between amino acid residues and ligands. The in vitro screening showed that the compounds AI6, Ca2, and D8 were potent, produced 4.756, 3.608 and 5.211 µM of IC50 respectively, whereas the standard Nifedipine showed the potency of 1.304 µM of IC50. The 3D QSAR study explained the importance of different steric and electrostatic parameters and their correlation for L type calcium channel blocking activity. CONCLUSION: This study showed that the chalcone scaffold with NO donor capacity is promising for designing novel calcium channel blockers to treat vascular disorders.

Synthesis and Modeling Studies of Furoxan Coupled Spiro-Isoquinolino Piperidine Derivatives as NO Releasing PDE 5 Inhibitors.

Nitric oxide (NO) is considered to be one of the most important intracellular messengers that play an active role as neurotransmitter in regulation of various cardiovascular physiological and pathological processes. Nitric oxide (NO) is a major factor in penile erectile function. NO exerts a relaxing action on corpus cavernosum and penile arteries by activating smooth muscle soluble guanylate cyclase and increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP). Phophodiesterase (PDE) inhibitors have potential therapeutic applications. NO hybridization has been found to improve and extend the pharmacological properties of the parental compound. The present study describes the synthesis of novel furoxan coupled spiro-isoquinolino-piperidine derivatives and their smooth muscle relaxant activity. The study reveals that, particularly 10d (1.50 ± 0.6) and 10g (1.65 ± 0.7) are moderate PDE 5 inhibitors as compared to Sidenafil (1.43 ± 0.5). The observed effect was explained by molecular modelling studies on phosphodiesterase.

Multi-Targeted Design and Development of Dihydroisoquinolines as Potent Antimalarials.

BACKGROUND: Malaria is a serious parasitic infection with greater morbidity and motility in recent decades. Cysteine protease and DHODH enzyme serve as a potential target for antimalarial agents which inhibit parasite multiplication in the erythrocyte stage. Development of new leads which specifically target cysteine protease and DHODH enzyme can reduce the side effects and overcome multidrug resistance. OBJECTIVES: Representing the design and development of antimalarial agents by targeting cysteine protease and DHODH (Dihydroorotate dehydrogenase) enzyme by structure-based drug design. METHODS: In present work, the rational development of antimalarial agents by targeting cysteine protease and DHODH has been made by integrating binding confirmation from virtual analysis and synthetic procedures. RESULTS: A novel series of dihydroisoquinolines was designed by structure-based drug design. Compounds from the dataset were screened for interaction at the target site by performing molecular docking study and subsequently, all molecules were screened for drug-like properties and toxicity, prior to synthesis molecules subjected to virtual filters. Designed molecules which exceed these virtual filters were synthesized, characterized and finally screened for antimalarial activity. CONCLUSION: In this work, it has been observed that compound A1, A5, A6 and A9 showed desirable biological activity towards targets and also specific hydrogen bonding interaction with the targets. Further optimization in leads yields a drug-like candidate and may overcome multidrug resistance.

Quantitative Structure-Property Relationship Approach in Formulation Development: an Overview.

Chemoinformatics is emerging as a new trend to set drug discovery which correlates the relationship between structure and biological functions. The main aim of chemoinformatics refers to analyzing the similarity among molecules, searching the molecules in the structural database, finding potential drug molecule and their property. One of the key fields in chemoinformatics is quantitative structure-property relationship (QSPR), which is an alternative process to predict the various physicochemical and biopharmaceutical properties. This methodology expresses molecules via various numerical values or properties (descriptors), which encodes the structural characteristics of molecules and further used to calculate physicochemical properties of the molecule. The established QSPR model could be used to predict the properties of compounds that have been measured or even have been unknown, which ultimately accelerates the development process of a new molecule or the product. The formulation characteristics (drug release, transportability, bioavailability) can be predicted with the integration of QSPR approach. Therefore, QSPR modeling is an emerging trend to skip conventional drug as well as formulation development process. The current review highlights the overall process involved in the application of the QSPR approach in formulation development.

Development of leads targeting ER-α in breast cancer: An in silico exploration from natural domain.

The steroid, estrogen has been recognized as being important for stimulating the growth of breast cancers primarily mediated via the steroidal estrogen receptor-α (ER-α). Inhibition of estrogen activity by small molecules with increased target specificity has proven to be an effective treatment for breast cancer. After the success stories of SERMs and fulvestrant, there is a need for the development of new small molecule modulating ER-α is due to developing resistance and side effects to current breast cancer therapy. In this pursuit, we virtually screened 227 chemically diverse bioactive natural products to get the best hits having an ER-α binding affinity. The docking scores and protein-ligand interactions of the obtained hits were emulated with the clinically used selective estrogen modulators and ER-antagonists. The results revealed 18 potential hits, which were putatively classified as hits belonging to ER agonists, modulators, and antagonists. Furthermore, as most of the hits were found to comprise the chromene nucleus, the 2D and 3D QSAR studies were performed using a set of natural products and synthesized compounds containing this scaffold, to understand the structural requirements for improving activity against breast cancer. Additionally, a pharmacophore model was generated to investigate the pharmacophoric features of the explored scaffolds for an optimal anticancer activity. The results signify that these compounds with structural modification could serve as potential leads in the drug discovery process for the treatment of breast cancer.

Computational Modeling of Polymeric Physicochemical Properties for Formulation Development of a Drug Containing Basic Functionality.

In the present research, predictive models were developed by correlating polymeric properties with characteristics of a formulation containing a drug with basic heterocycle (glipizide). Glipizide tablets containing different polymers from 3 categories (immediate, moderate, and extended release) were prepared and evaluated. Dissolution kinetics indicated Korsmeyer-Peppas as the best-fit model, whereas transportability was influenced by release rate and hydrophobicity of the drug. Calculated polymeric descriptors were correlated with formulation properties for the development of predictive quantitative structure-property relationship models. Regression coefficients and subsequent validation of developed models indicated potential predictability of the model for formulation properties containing any drug with basic heterocycle. Such models could also help to decide the formulation composition for desired characteristics with saving of time and formulation cost.

Hyperoxaluria leads to dysbiosis and drives selective enrichment of oxalate metabolizing bacterial species in recurrent kidney stone endures.

Hyperoxaluria due to endogenously synthesized and exogenously ingested oxalates is a leading cause of recurrent oxalate stone formations. Even though, humans largely rely on gut microbiota for oxalate homeostasis, hyperoxaluria associated gut microbiota features remain largely unknown. Based on 16S rRNA gene amplicons, targeted metagenomic sequencing of formyl-CoA transferase (frc) gene and qPCR assay, we demonstrate a selective enrichment of Oxalate Metabolizing Bacterial Species (OMBS) in hyperoxaluria condition. Interestingly, higher than usual concentration of oxalate was found inhibitory to many gut microbes, including Oxalobacter formigenes, a well-characterized OMBS. In addition a concomitant enrichment of acid tolerant pathobionts in recurrent stone sufferers is observed. Further, specific enzymes participating in oxalate metabolism are found augmented in stone endures. Additionally, hyperoxaluria driven dysbiosis was found to be associated with oxalate content, stone episodes and colonization pattern of Oxalobacter formigenes. Thus, we rationalize the first in-depth surveillance of OMBS in the human gut and their association with hyperoxaluria. Our findings can be utilized in the treatment of hyperoxaluria associated recurrent stone episodes.

Quantitative structure property relationship modeling of excipient properties for prediction of formulation characteristics.

Quantitative structure property relationship (QSPR) is used to relate the excipient descriptors with the formulation properties. A QSPR model is developed by regression analysis of selected descriptors contributing towards the targeted formulation properties. Developed QSPR model is validated by the true external method where it showed good accuracy and precision in predicting the formulation composition as experimental t90% (61.35min) is observed very close to predicted t90% (67.37min). Hence, QSPR approach saves resources by predicting drug release from an unformulated formulation; avoiding repetitive trials in the development of a new formulation and/or optimization of existing one.

Implications of formulation design on lipid-based nanostructured carrier system for drug delivery to brain.

CONTEXT & OBJECTIVE: The aim of present investigation was to formulate and develop lipid-based nanostructured carriers (NLCs) containing Idebenone (IDE) for delivery to brain. Attempts have been made to evaluate IDE NLCs for its pharmacokinetic and pharmacodynamic profile through the objective of enhancement in bioavailability and effectivity of drug. METHODS: Nanoprecipitation technique was used for development of drug loaded NLCs. The components solid lipid Precirol ATO 5, oil Miglyol 840, surfactants Tween 80 and Labrasol have been screened out for formulation development by consideration of preformulation parameters including solubility, Required Hydrophilic lipophilic balance (HLB) of lipids and stability study. Developed IDE NLCs were subjected for particle size, zeta potential, entrapment efficiency (%EE), crystallographic investigation, transmission electron microscopy, in vitro drug release, pharmacokinetics, in vivo and stability study. RESULTS: Formulation under investigation has particle size 174.1 ± 2.6 nm, zeta potential -18.65 ± 1.13 mV and% EE 90.68 ± 2.90. Crystallographic studies exemplified for partial amorphization of IDE by molecularly dispersion within lipid crust. IDE NLCs showed drug release 93.56 ± 0.39% at end of 24 h by following Higuchi model which necessitates for appropriate drug delivery with enhancement in bioavailability of drug by 4.6-fold in plasma and 2.8-fold in brain over plain drug loaded aqueous dispersions. In vivo studies revealed that effect of drug was enhanced by prepared lipid nanocarriers. CONCLUSIONS: IDE lipid-based nanostructured carriers could have potential for efficient drug delivery to brain with enhancement in bioavailability of drug over the conventional formulations.

Experimental and chemoinformatics evaluation of some physicochemical properties of excipients influencing release kinetics of the acidic drug ibuprofen.

In the present study, ibuprofen, a nonsteroidal anti-inflammatory drug was used in the formulation of tablets using three polymers representing different categories (immediate, moderate and extended release). Prepared tablets were evaluated for different post-compression parameters including dissolution and transportability studies. In vitro dissolution studies indicated Korsmeyer-Peppas as a best fit model, however, the transport of the drug was found to be influenced by its rate of release. A total of 118 molecular descriptors representing physicochemical and topological properties of polymeric structure was calculated and correlated with formulation characteristics for model generation. Further, predictive quantitative-structure property relationship models were developed for correlating polymeric descriptors with formulation properties containing acidic drug (ibuprofen). Developed models exhibited good predictability for formulation characteristics as indicated by squared correlation coefficients (>0.9). Such models could have an ability to predict the formulation properties as well as composition for desired characteristics with saving of time, material and cost.

In-silico docking based design and synthesis of [1H,3H] imidazo[4,5-b] pyridines as lumazine synthase inhibitors for their effective antimicrobial activity.

PURPOSE: The imidazopyridine moiety is important pharmacophore that has proven to be useful for a number of biologically relevant targets, also reported to display antibacterial, antifungal, antiviral properties. Riboflavin biosynthesis involving catalytic step of Lumazine synthase is absent in animals and human, but present in microorganism, one of marked advantage of this study. Still, this path is not exploited as antiinfective target. Here, we proposed different interactions between [1H,3H] imidazo[4,5-b] pyridine test ligands and target protein Lumazine synthase (protein Data Bank 2C92), one-step synthesis of title compounds and further evaluation of them for in vitro antimicrobial activity. MATERIALS AND METHODS: Active pocket of the target protein involved in the interaction with the test ligands molecules was found using Biopredicta tools in VLifeMDS 4.3 Suite. In-silico docking suggests H-bonding, hydrophobic interaction, charge interaction, aromatic interaction, and Vanderwaal forces responsible for stabilizing enzyme-inhibitor complex. Disc diffusion assay method was used for in vitro antimicrobial screening. RESULTS AND DISCUSSION: Investigation of possible interaction between test ligands and target lumazine synthase of Mycobacterium tuberculosis suggested 1i and 2f as best fit candidates showing hydrogen bonding, hydrophobic, aromatic and Vanderwaal's forces. Among all derivatives 1g, 1j, 1k, 1l, 2a, 2c, 2d, 2e, 2h, and 2j exhibited potent activities against bacteria and fungi compared to the standard Ciprofloxacin and Fluconazole, respectively. The superiority of 1H imidazo [4,5-b] pyridine compounds having R' = Cl >No2 > NH2 at the phenyl/aliphatic moiety resident on the imidazopyridine, whereas leading 3H imidazo[4,5-b] pyridine compounds containing R/Ar = Cl > No2 > NH2> OCH3 substituents on the 2(nd) position of imidazole.

Polymers influencing transportability profile of drug.

Drug release from various polymers is generally governed by the type of polymer/s incorporated in the formulation and mechanism of drug release from polymer/s. A single polymer may show one or more mechanisms of drug release out of which one mechanism is majorly followed for drug release. Some of the common mechanisms of drug release from polymers were, diffusion, swelling, matrix release, leaching of drug, etc. Mechanism or rate of drug release from a polymer or a combination of polymers can be predicted by using different computational methods or models. These models were capable of predicting drug release from its dosage form in advance without actual formulation and testing of drug release from dosage form. Quantitative structure-property relationship (QSPR) is an important tool used in the prediction of various physicochemical properties of actives as well as inactives. Since last several decades QSPR has been applied in new drug development for reducing the total number of drugs to be synthesized, as it involves a selection of the most desirable compound of interest. This technique was also applied in predicting in vivo performance of drug/s for various parameters. QSPR serves as a predictive tool to correlate structural descriptors of molecules with biological as well as physicochemical properties. Several researchers have contributed at different extents in this area to modify various properties of pharmaceuticals. The present review is focused on a study of different polymers that influence the transportability profiles of drugs along with the application of QSPR either to study different properties of polymers that regulate drug release or in predicting drug transportability from different polymer systems used in formulations.

Pharmacophore Identification and QSAR Studies on Substituted Benzoxazinone as Antiplatelet Agents: kNN-MFA Approach.

The three-dimensional quantitative structure-activity relationship (3D-QSAR) and pharmacophore identification studies on 28 substituted benzoxazinone derivatives as antiplatelet agents have been carried out. Multiple linear regression (MLR) method was applied for QSAR model development considering training and test set approaches with various feature selection methods. Stepwise (SW), simulated annealing (SA) and genetic algorithm (GA) were applied to derive QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The results of pharmacophore identification studies showed that hydrogen bond accepters, aromatic and hydrophobic, are the important features for antiplatelet activity. The selected best 3D kNN-MFA model A has a training set of 23 molecules and test set of 5 molecules with validation (q(2)) and cross validation (pred_r(2)) values 0.9739 and 0.8217, respectively. Additionally, the selected best 3D QSAR (MLR) model B has a training set of 23 molecules and test set of 5 molecules with validation (r(2)) and cross validation (pred_r(2)) values of 0.9435 and 0.7663, respectively, and four descriptors at the grid points S_123, E_407, E_311 and H_605. The information rendered by 3D-QSAR models may lead to a better understanding and designing of novel potent antiplatelet molecules.