Oleogels: Versatile Novel Semi-Solid System for Pharmaceuticals.

Oleogels is a novel semi-solid system, focusing on its composition, formulation, characterization, and diverse pharmaceutical applications. Due to their stability, smoothness, and controlled release qualities, oleogels are frequently utilized in food, cosmetics, and medicinal products. Oleogels are meticulously formulated by combining oleogelators like waxes, fatty acids, ethyl cellulose, and phytosterols with edible oils, leading to a nuanced understanding of their impact on rheological characteristics. They can be characterized by methods like visual inspection, texture analysis, rheological measurements, gelation tests, and microscopy. The applications of oleogels are explored in diverse fields such as nutraceuticals, cosmetics, food, lubricants, and pharmaceutics. Oleogels have applications in topical, transdermal, and ocular drug delivery, showcasing their potential for revolutionizing drug administration. This review aims to enhance the understanding of oleogels, contributing to the evolving landscape of pharmaceutical formulations. Oleogels emerge as a versatile and promising solution, offering substantial potential for innovation in drug delivery and formulation practices.

Design of floating formulations and antiulcer activity of Desmostachya bipinnata.

The study aims to design and optimize the floating formulations of the aqueous extract of Desmostachya bipinnata (ADB) to treat peptic ulcers. The trial concentrations of HPMC E50, HPMC K4M, and Carbopol 940 were used as factors, and floating lag time, total floating time, and % drug release at 12 h were used as responses. The formulation underwent evaluation for different parameters: aspirin-induced ulcers in rats assessed the antiulcer activity, and X-ray studies in rabbits evaluated the gastroretentive nature. The optimized formulation has shown a floating lag time of 32 s and floated in the gastric medium for more than 9 h with a maximum drug release of 93% at the end of 12 h by following the Korsmeyer-Peppas drug release mechanism. The optimized formulation has good flow properties. The FT-IR, DSC, and XRD studies show ADB and excipients didn't show any incompatibility. The formulation has shown significant antiulcer activity against aspirin-induced ulcers in rats, with an ulcer index of 3.38 ± 0.24 and inhibition of 76.67 ± 0.56%. The in vivo X-ray imaging proved the gastric retention of the formulations for more than 8 h. The results of the formulations demonstrate the floating ability and sustained drug release of the tablet responsible for treating peptic ulcers to show a localized effect in the gastric region and to maintain the ROS levels.

Molecular dynamics and structure-based virtual screening and identification of natural compounds as Wnt signaling modulators: possible therapeutics for Alzheimer's disease.

Wnt signaling pathway is an evolutionarily conserved pathway responsible for neurogenesis, axon outgrowth, neuronal polarity, synapse formation, and maintenance. Downregulation of Wnt signaling has been found in patients with Alzheimer's disease (AD). Several experimental approaches to activate Wnt signaling pathway have proven to be beneficial in alleviating AD, which is one of the new therapeutic approaches for AD. The current study focuses on the computational structure-based virtual screening followed by the identification of potential phytomolecules targeting different markers of Wnt signaling like WIF1, DKK1, LRP6, GSK-3ß, and acetylcholine esterase. Initially, screening of 1924 compounds from the plant-based library of Zinc database was done for the selected five proteins using docking approach followed by MM-GBSA calculations. The top five hit molecules were identified for each protein. Based on docking score, and binding interactions, the top two hit molecules for each protein were selected as promising molecules for the molecular dynamic (MD) simulation study with the five proteins. Therefore, from this in silico based study, we report that Mangiferin could be a potential molecule targeting Wnt signaling pathway modulating the LRP6 activity, Baicalin for AChE activity, Chebulic acid for DKK1, ZINC103539689 for WIF1, and Morin for GSk-3ß protein. However, further validation of the activity is warranted based on in vivo and in vitro experiments for better understanding and strong claim. This study provides an in silico approach for the identification of modulators of the Wnt signaling pathway as a new therapeutic approach for AD.

Structure-based docking, pharmacokinetic evaluation, and molecular dynamics-guided evaluation of traditional formulation against SARS-CoV-2 spike protein receptor bind domain and ACE2 receptor complex.

There is an urgent need for reliable cure and preventive measures in this hour of the outbreak of SARS-CoV-2. Siddha- and Ayurvedic-based classical formulations have antiviral properties and great potential therapeutic choice in this pandemic situation. In the current study, in silico-based analysis for the binding potential of phytoconstituents from the classical formulations suggested by the Ministry of Ayush (Kabasura Kudineer, Shwas Kuthar Rasa with Kantakari and pippali churna, Talisadi churna) to the interface domain of the SARS-CoV-2 receptor-binding domain and angiotensin-converting enzyme 2 was performed. Maestro software from Schrodinger and tools like Glide Docking, induced fit docking, MM-GBSA, molecular dynamics (MD) simulation, and thermal MM-GBSA was used to analyze the binding of protein PDB ID:6VW1 and the selected 133 ligands in comparison with drug molecules like favipiravir and ribavirin. QikProp-based ADMET evaluation of all the phytoconstituents found them nontoxic and with drug-like properties. Selection of top ten ligands was made based on docking score for further MM-GBSA analysis. After performing IFD of top five molecules iso-chlorogenic acid, taxiphyllin, vasicine, catechin and caffeic acid, MD simulation and thermal MM-GBSA were done. Iso-chlorogenic acid had formed more stable interaction with key residue among all phytoconstituents. Computational-based study has highlighted the potential of the many constituents of traditional medicine to interact with the SARS-CoV-2 RBD and ACE2, which might stop the viral entry into the cell. However, in vivo experiments and clinical trials are necessary for supporting this claim. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11696-021-01917-z.

Structurally nanoengineered antimicrobial peptide polymers: design, synthesis and biomedical applications.

Antimicrobial resistance not only increases the contagiousness of infectious diseases but also a threat for the future as it is one of the health care concern around the globe. Conventional antibiotics are unsuccessful in combating chronic infections caused by multidrug-resistant (MDR) bacteria, therefore it is important to design and develop novel strategies to tackle this problems. Among various novel strategies, Structurally Nanoengineered Antimicrobial Peptide Polymers (SNAPPs) have been introduced in recent years to overcome this global health care issue and they are found to be more efficient in their performance. Many facile methods are adapted to synthesize complex SNAPPs with required dimensions and unique functionalities. Their unique characteristics and remarkable properties have been exploited for their immense applications in various fields including biomedicine, targeting therapies, gene delivery, bioimaging, and many more. This review article deals with its background, design, synthesis, mechanism of action, and wider applications in various fields of SNAPPs.

Antimicrobial peptide polymers: no escape to ESKAPE pathogens-a review.

Antimicrobial resistance (AMR) is one of the significant clinical challenges and also an emerging area of concern arising from nosocomial infections of ESKAPE pathogens, which has been on the rise in both the developed and developing countries alike. These pathogens/superbugs can undergo rapid mutagenesis, which helps them to generate resistance against antimicrobials in addition to the patient's non-adherence to the antibiotic regimen. Sticking to the idea of a 'one-size-fits-all' approach has led to the inappropriate administration of antibiotics resulting in augmentation of antimicrobial resistance. Antimicrobial peptides (AMPs) are the natural host defense peptides that have gained attention in the field of AMR, and recently, synthetic AMPs are well studied to overcome the drawbacks of natural counterparts. This review deals with the novel techniques utilizing the bacteriolytic activity of natural AMPs. The effective localization of these peptides onto the negatively charged bacterial surface by using nanocarriers and structurally nanoengineered antimicrobial peptide polymers (SNAPPs) owing to its smaller size and better antimicrobial activity is also described here.

Evaluation of a mouthrinse containing guava leaf extract as part of comprehensive oral care regimen- a randomized placebo-controlled clinical trial.

BACKGROUND: The control of biofilm adherence on tooth surface has always been the keystone of periodontal therapeutic systems. However, prevalence of gingivitis suggest inadequacy of self-performed oral hygiene measures and need for adjunctive aid for mechanical plaque control. Oral rinses containing chlorhexidine, has been widely used however, with certain limitations. Herbal products have been used widely reflecting its action as alternative and complementary remedy. Hence, the purpose of the present study was to evaluate the antimicrobial and antioxidant efficacy of a Guava leaf extract based mouthrinse in patients with chronic generalized gingivitis as an adjunct to oral prophylaxis. METHODS: Sixty subjects (n = 20) in compliance with the inclusion criteria were randomly assigned to one of the 3 study groups i.e. Group A- 0.15%Guava mouth rinse, Group B- 0.2% Chlorhexidine (CHX) mouth rinse, Group C- Distilled water (placebo). All the participants received professional oral prophylaxis and were dispensed with experimental mouth rinses and instructed to use for period of 30 days. Clinical parameters such as gingival index, plaque index along with microbial colony forming units using plaque samples and antioxidant levels in saliva were estimated at baseline, 30 and 90 days' time intervals. RESULTS: All 3 groups showed gradual reduction in GI, PI and microbial counts. Considering the mean scores of recorded parameters at the scheduled time intervals, notable changes were observed between chlorhexidine and guava mouth rinse compared to placebo group. Although there was improvement in the antioxidant status in all study participants, yet there was no statistically significant difference observed. CONCLUSION: Guava mouth rinse can be used as an empirical adjunct to professional oral prophylaxis owing to its multifactorial properties and favourable acceptance. However, long term studies need to be conducted to validate its use for an extended period of time. TRIAL REGISTRATION: The clinical trial has been prospectively registered on 17th February 2017 by the Clinical Trials Registry-India (CTRI/2017/02/007898).

2,5-Dimethyl-4-hydroxy-3(2H)-furanone as an Anti-biofilm Agent Against Non-Candida albicans Candida Species.

BACKGROUND: The predominance of non-Candida albicans Candida (NCAC) species causing healthcare-associated infections has increased over the last decade pertaining to their ability to form biofilms on medical devices. These biofilm-associated infections are challenging to treat as they are resistant to antifungal agents and evade host-immune response resulting in a high risk of device failure or biomaterial removal. Thus, to minimize the risk of biofilm-associated infections, preventing biofilm formation is the best approach which is mediated by the quorum quenching process. METHODS: The present study investigated the modulatory effect of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) on NCAC biofilm formation and also assessed the effect of the DMHF-coated catheters on biofilm formation of NCAC. The NCAC isolates studied were Candida tropicalis, Candida glabrata and Candida krusei isolated from catheter tip, urine and blood, respectively. RESULTS: DMHF at a concentration of 30 µg/mL showed an inhibitory effect against NCAC biofilms at various stages and was statistically significant (p ≤ 0.05) against the various concentrations (50-5 µg/mL) tested and also among the three phases of experiment. The furanone content on coated catheters ranged from 170 to 750 µg and release of furanone from the coated catheter was about 15 µg for 30 days. The effect of DMHF-coated catheters on NCAC biofilm formation was observed by the scanning electron microscopy which revealed the absence of NCAC adherence on DMHF-coated catheters. DISCUSSION: This study provides a design to develop furanone-coated biomaterials which could be implemented in healthcare settings to reduce medical device-associated infections. The excellent biological performance, combined with their antimicrobial properties, suggests that 2,5-dimethyl-4-hydroxy-3(2H)-furanone could be an effective anti-infective coating for implantable devices.

Inclusion Complexation of Etodolac with Hydroxypropyl-beta-cyclodextrin and Auxiliary Agents: Formulation Characterization and Molecular Modeling Studies.

The present investigation was aimed to prepare inclusion complexes of a therapeutically important nonsteroidal anti-inflammatory drug, etodolac (ETD) with hydroxypropyl-beta-cyclodextrin (HP-ß-CD) and to study the effect of l-arginine (l-Arg) as an auxiliary agent on the complexation efficiency of HP-ß-CD to improve aqueous solubility and the dissolution property of ETD. The binary and ternary complexes were prepared by physical mixing, coevaporation, and spray drying methods. The complexes were characterized using differential scanning colorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD) studies. The mechanism of inclusion interaction of guest and host was established through 1H NMR, molecular docking, and molecular dynamics studies. On the basis of preliminary screening studies, l-Arg was found to be the most efficient auxiliary agent for the present research problem. The change in crystallinity of ETD was evident from DSC and PXRD studies which indicated the formation of new solid forms. A remarkable increase in apparent stability constant (Kc) and complexation efficiency (CE) of HP-ß-CD was observed in the presence of l-Arg in ternary complexes with improvement in solubility and dissolution of ETD than binary complexes. However, inclusion complexes of ETD obtained by computational studies is in good correlation with the results obtained through experimental methods. More stable complex formation with l-Arg was confirmed by molecular simulation studies too. Thus, the present study led to the conclusion that the ternary complex of ETD-HP-ß-CD-l-Arg could be an innovative approach to augment the solubility and dissolution behavior of ETD.

Formulation and assessment of biological properties of garcinia indica fruit extract mouthrinse as an adjunct to oral hygiene regimen: an in vitro analysis.

The prevalence of gingivitis is substantial within the general population, necessitating rigorous oral hygiene maintenance. OBJECTIVE: This study assessed a Garcinia indica (GI) fruit extract-based mouthrinse, comparing it to a 0.1% turmeric mouthrinse and a 0.2% Chlorhexidine (CHX) mouthrinse. The evaluation encompassed substantivity, staining potential, antimicrobial efficacy and cytocompatibility. METHODOLOGY: The study employed 182 tooth sections. For antimicrobial analysis, 64 extracted human teeth coated with a polymicrobial biofilm were divided into four groups, each receiving an experimental mouthrinse or serving as a control group with distilled water. Microbial reduction was assessed through colony forming units (CFU). Substantivity was evaluated on 54 human tooth sections using a UV spectrophotometer, while staining potential was examined on 64 tooth sections. Cytocompatibility was tested using colorimetric assay to determine non-toxic levels of 0.2% GI fruit extract, 0.1% Turmeric, and 0.2% CHX. RESULTS: Data were analysed with one-way ANOVA (α=0.05). Cell viability was highly significant (p<0.001) in the 0.2% GI group (64.1±0.29) compared to 0.1% Turmeric (40.2±0.34) and 0.2% CHX (10.95±1.40). For antimicrobial activity, both 0.2% GI (20.18±4.81) and 0.2% CHX (28.22±5.41) exhibited no significant difference (P>0.05) at end of 12 hours. However, 0.1% Turmeric showed minimal CFU reduction (P<0.001). Substantivity results at 360 minutes indicated statistically significant higher mean release rate in 0.1%Turmeric (12.47±5.84 ) when compared to 0.2% GI (5.02±3.04) and 0.2% CHX (4.13±2.25) (p<0.001). The overall discoloration changes (∆E) were more prominent in the 0.2% CHX group (18.65±8.3) compared to 0.2% GI (7.61±2.4) and 0.1% Turmeric (7.32±4.9) (P<0.001). CONCLUSION: This study supports 0.2% GI and 0.1% Turmeric mouth rinses as potential natural alternatives to chemical mouth rinses. These findings highlight viability of these natural supplements in oral healthcare.

In-silico lead identification of the pan-mutant IDH1 and IDH2 inhibitors to target glioblastoma.

Glioblastoma (GBM) is an aggressive malignant type of brain tumor. Targeting one single intracellular pathway might not alleviate the disease, rather it activates the other molecular pathways that lead to the worsening of the disease condition. Therefore, in this study, we attempted to target both isocitrate dehydrogenase 1 (IDH1) and IDH2, which are one of the most commonly mutated proteins in GBM and other cancer types. Here, standard precision and extra precision docking, IFD, MM-GBSA, QikProp, and molecular dynamics (MD) simulation were performed to identify the potential dual inhibitor for IDH1 and IDH2 from the enamine database containing 59,161 ligands. Upon docking the ligands with IDH1 (PDB: 6VEI) and IDH2 (PDB: 6VFZ), the top eight ligands were selected, based on the XP Glide score. These ligands produced favourable MMGBSA scores and ADME characteristics. Finally, the top four ligands 12953, 44825, 51295, and 53210 were subjected to MD analysis. Interestingly, 53210 showed maximum interaction with Gln 277 for 99% in IDH1 and Gln 316 for 100% in IDH2, which are the crucial amino acids for the inhibitory function of IDH1 and IDH2 to target GBM. Therefore, the present study attempts to identify the novel molecules which could possess a pan-inhibitory action on both IDH1 and IDH that could be crucial in the management of GBM. Yet further evaluation involving in vitro and in vivo studies is warranted to support the data in our current study.Communicated by Ramaswamy H. Sarma.

Co-delivery of lapatinib and 5-fluorouracil transfersomes using transpapillary iontophoresis for breast cancer therapy.

Combination chemotherapy, involving the intervention of two or more anti-neoplastic agents has been the cornerstone in breast cancer treatment, owing to the applications it holds in contrast to the mono-therapy approach. This research predominantly focussed on proving the synergy between Lapatinib (LPT) and 5-Fluorouracil (5-FU) and further enhancing its localized permeation via transfersome-loaded delivery and iontophoresis to treat breast tumors. The IC50 values for LPT and 5-FU were found to be 19.38 µg/ml and 5.7 µg/ml respectively and their synergistic effect was proven by the Chou-Talalay assay using CompuSyn software. Furthermore, LPT and 5-FU were encapsulated within transfersomes and administered via the transpapillary route. The drug-loaded carriers were characterized for their particle size, polydispersity index, zeta potential, and entrapment efficiency. The ex vivo rat skin permeation studies indicated that when compared to LPT dispersion and 5-FU solution, drug-loaded transfersomes exhibited better permeability and their transpapillary permeation was enhanced on using iontophoresis. Moreover, both LPT and 5-FU transfersomes were found to be stable for 3 months when stored at a temperature of 5 ± 3 °C. The results indicated that this treatment strategy could be an effective approach in contrast to some of the conventional treatments employed to date.

Polymeric functionalization of mesoporous silica nanoparticles: Biomedical insights.

Mesoporous silica nanoparticles (MSNs) endowed with polymer coatings present a versatile platform, offering notable advantages such as targeted, pH-controlled, and stimuli-responsive drug delivery. Surface functionalization, particularly through amine and carboxyl modification, enhances their suitability for polymerization, thereby augmenting their versatility and applicability. This review delves into the diverse therapeutic realms benefiting from polymer-coated MSNs, including photodynamic therapy (PDT), photothermal therapy (PTT), chemotherapy, RNA delivery, wound healing, tissue engineering, food packaging, and neurodegenerative disorder treatment. The multifaceted potential of polymer-coated MSNs underscores their significance as a focal point for future research endeavors and clinical applications. A comprehensive analysis of various polymers and biopolymers, such as polydopamine, chitosan, polyethylene glycol, polycaprolactone, alginate, gelatin, albumin, and others, is conducted to elucidate their advantages, benefits, and utilization across biomedical disciplines. Furthermore, this review extends its scope beyond polymerization and biomedical applications to encompass topics such as surface functionalization, chemical modification of MSNs, recent patents in the MSN domain, and the toxicity associated with MSN polymerization. Additionally, a brief discourse on green polymers is also included in review, highlighting their potential for fostering a sustainable future.

Multi-Targeting Approach in Selection of Potential Molecule for COVID-19 Treatment.

The coronavirus disease (COVID-19) is a pandemic that started in the City of Wuhan, Hubei Province, China, caused by the spread of coronavirus (SARS-CoV-2). Drug discovery teams around the globe are in a race to develop a medicine for its management. It takes time for a novel molecule to enter the market, and the ideal way is to exploit the already approved drugs and repurpose them therapeutically. We have attempted to screen selected molecules with an affinity towards multiple protein targets in COVID-19 using the Schrödinger suit for in silico predictions. The proteins selected were angiotensin-converting enzyme-2 (ACE2), main protease (MPro), and spike protein. The molecular docking, prime MM-GBSA, induced-fit docking (IFD), and molecular dynamics (MD) simulations were used to identify the most suitable molecule that forms a stable interaction with the selected viral proteins. The ligand-binding stability for the proteins PDB-IDs 1ZV8 (spike protein), 5R82 (Mpro), and 6M1D (ACE2), was in the order of nintedanib > quercetin, nintedanib > darunavir, nintedanib > baricitinib, respectively. The MM-GBSA, IFD, and MD simulation studies imply that the drug nintedanib has the highest binding stability among the shortlisted. Nintedanib, primarily used for idiopathic pulmonary fibrosis, can be considered for repurposing for us against COVID-19.

Design, development and evaluation of Resveratrol transdermal patches for breast cancer therapy.

Resveratrol (RVT) is a polyphenolic phytoestrogen which has shown antiproliferative activity in breast cancer. However, its low bioavailability and short half-life have restricted its use. The current study aimed to develop transdermal patches of RVT and evaluate its site-specific delivery for breast cancer therapy. Different penetration enhancers were screened using a computational tool, quantitative structure propery relationship (QSPR). The best permeation of RVT was observed in a patch comprising hydroxypropyl methylcellulose (HPMC) E15LV: HPMC-K4M: polyvinyl pyrrolidone (PVP) K30 in the ratio of 3:1:2 as release controlling polymers with Glycerol:Capryol 90 (4:1) as penetration enhancer and plasticizer. To assess the localized delivery of RVT, the patch was applied to the breast of female rats. Higher breast tissue disposition with lower systemic concentration was observed compared to oral administration, demonstrated by increased AUC and MRT. Further, the optimized RVT patches were tested in 7,12-Dimethylbenz[a]anthracene (DMBA) induced rat mammary cancer. Compared to oral RVT, the application of RVT tansdermal patches significantly reduced the tumor volume and serum CA 15-3, a cancer biomarker. Thus, the RVT transdermal patch may be a viable approach for ensuring high local concentration of drug for site-specific delivery in breast cancer therapy.

Transforming Wound Management: Nanomaterials and Their Clinical Impact.

Wound healing is a complex process that can be further complicated in chronic wounds, leading to prolonged healing times, high healthcare costs, and potential patient morbidity. Nanotechnology has shown great promise in developing advanced wound dressings that promote wound healing and prevent infection. The review article presents a comprehensive search strategy that was applied to four databases, namely Scopus, Web of Science, PubMed, and Google Scholar, using specific keywords and inclusion/exclusion criteria to select a representative sample of 164 research articles published between 2001 and 2023. This review article provides an updated overview of the different types of nanomaterials used in wound dressings, including nanofibers, nanocomposites, silver-based nanoparticles, lipid nanoparticles, and polymeric nanoparticles. Several recent studies have shown the potential benefits of using nanomaterials in wound care, including the use of hydrogel/nano silver-based dressings in treating diabetic foot wounds, the use of copper oxide-infused dressings in difficult-to-treat wounds, and the use of chitosan nanofiber mats in burn dressings. Overall, developing nanomaterials in wound care has complemented nanotechnology in drug delivery systems, providing biocompatible and biodegradable nanomaterials that enhance wound healing and provide sustained drug release. Wound dressings are an effective and convenient method of wound care that can prevent wound contamination, support the injured area, control hemorrhaging, and reduce pain and inflammation. This review article provides valuable insights into the potential role of individual nanoformulations used in wound dressings in promoting wound healing and preventing infections, and serves as an excellent resource for clinicians, researchers, and patients seeking improved healing outcomes.

Controlled Release Technologies for Chronotherapy: Current Status and Future Perspectives.

The expression "as sure as night follows a day" emulates those certain cycles in the environment that are always stable. Circadian rhythms are a group of processes that occur within the body in synchronisation with the external factors in a 24 h cycle. Changes in lifestyle and work shifts have disrupted these stable rhythms, which is a leading cause of lifestyle diseases. Associations between these biological clocks and diseases are abundant. However, it is also known that certain drugs work more efficiently and have minimum toxicity when given during a particular phase of the circadian cycle. Chronotherapeutics focuses on treating diseases according to the endogenous processes which mediate xenobiotic metabolism and drug response at a cellular level. Therefore, treatment of those diseases that show aggravation of symptoms according to the circadian rhythms at a particular time is highly beneficial by chronotherapy. In this article, we have emphasised how the changes in rhythms caused diseases and how chronotherapeutic approaches such as controlled drug release technologies can be a better option for these circadian manipulations that seem to influence all types of disease conditions.

Computational drug repurposing of Akt-1 allosteric inhibitors for non-small cell lung cancer.

Non-small cell lung carcinomas (NSCLC) are the predominant form of lung malignancy and the reason for the highest number of cancer-related deaths. Widespread deregulation of Akt, a serine/threonine kinase, has been reported in NSCLC. Allosteric Akt inhibitors bind in the space separating the Pleckstrin homology (PH) and catalytic domains, typically with tryptophan residue (Trp-80). This could decrease the regulatory site phosphorylation by stabilizing the PH-in conformation. Hence, in this study, a computational investigation was undertaken to identify allosteric Akt-1 inhibitors from FDA-approved drugs. The molecules were docked at standard precision (SP) and extra-precision (XP), followed by Prime molecular mechanics-generalized Born surface area (MM-GBSA), and molecular dynamics (MD) simulations on selected hits. Post XP-docking, fourteen best hits were identified from a library of 2115 optimized FDA-approved compounds, demonstrating several beneficial interactions such as pi-pi stacking, pi-cation, direct, and water-bridged hydrogen bonds with the crucial residues (Trp-80 and Tyr-272) and several amino acid residues in the allosteric ligand-binding pocket of Akt-1. Subsequent MD simulations to verify the stability of chosen drugs to the Akt-1 allosteric site showed valganciclovir, dasatinib, indacaterol, and novobiocin to have high stability. Further, predictions for possible biological interactions were performed using computational tools such as ProTox-II, CLC-Pred, and PASSOnline. The shortlisted drugs open a new class of allosteric Akt-1 inhibitors for the therapy of NSCLC.

Identification of structural scaffold from interbioscreen (IBS) database to inhibit 3CLpro, PLpro, and RdRp of SARS-CoV-2 using molecular docking and dynamic simulation studies.

A novel coronavirus SARS-CoV-2 has caused a worldwide pandemic and remained a severe threat to the entire human population. Researchers worldwide are struggling to find an effective drug treatment to combat this deadly disease. Many FDA-approved drugs from varying inhibitory classes and plant-derived compounds are screened to combat this virus. Still, due to the lack of structural information and several mutations of this virus, initial drug discovery efforts have limited success. A high-resolution crystal structure of important proteins like the main protease (3CLpro) that are required for SARS-CoV-2 viral replication and polymerase (RdRp) and papain-like protease (PLpro) as a vital target in other coronaviruses still presents important targets for the drug discovery. With this knowledge, scaffold library of Interbioscreen (IBS) database was explored through molecular docking, MD simulation and postdynamic binding free energy studies. The 3D docking structures and simulation data for the IBS compounds was studied and articulated. The compounds were further evaluated for ADMET studies using QikProp and SwissADME tools. The results revealed that the natural compounds STOCK2N-00385, STOCK2N-00244, and STOCK2N-00331 interacted strongly with 3CLpro, PLpro, and RdRp, respectively, and ADMET data was also observed in the range of limits for almost all the compounds with few exceptions. Thus, it suggests that these compounds may be potential inhibitors of selected target proteins, or their structural scaffolds can be further optimized to obtain effective drug candidates for SARS-CoV-2. The findings of in-silico data need to be supported by in-vivo studies which could shed light on understanding the exact mode of inhibitory action.Communicated by Ramaswamy H. Sarma.

A computational-based approach to fabricate Ceritinib co-amorphous system using a novel co-former Rutin for bioavailability enhancement.

In this study, we used molecular simulations to design Ceritinib (CRT) co-amorphous materials (CAMs) with concurrent improvement in solubility and bioavailability. Computational modeling enabled us to select the co-former by estimating the binding energy and intermolecular interactions. Rutin (RTH) was selected as a co-former for CRT CAMs using the solvent evaporation method to anticipate simultaneous improvement of solubility and bioavailability. The solid state characterization using DSC, XRPD, FT-IR, and a significant shift in Gordon Taylor experimental Tg values of co-amorphous materials revealed single amorphous phase formation and intermolecular interactions between CRT and RTH. The co-amorphous materials exhibited physical stability for up to 4 months under dry conditions (40 °C). Further, co-amorphous materials maintained the supersaturation for 24 hrs and improved solubility as well as dissolution of CRT. CRT:RTH 1:1 CAMs improved the permeability of CRT by 2 fold, estimated by employing the everted gut sac method. The solubility advantage of CAMs was also reflected in pharmacokinetic parameters, with a 3.1-fold and 2-fold improvement of CRT:RTH 2:1 in CRT exposure (AUC 0-t) and plasma concentration (Cmax) compared to the physical mixture, respectively.