In silico analysis unravels the promising anticariogenic efficacy of fatty acids against dental caries causing Streptococcus mutans.

Globally, dental caries is a prevalent oral disease caused by cariogenic bacteria, primarily Streptococcus mutans. It establishes caries either through sucrose-dependent (via glycosyltransferases) or through sucrose-independent (via surface adhesins Antigen I/II) mechanism. Sortase A (srtA) attaches virulence-associated adhesins to host tissues. Because of their importance in the formation of caries, targeting these proteins is decisive in the development of new anticariogenic drugs. High-throughput virtual screening with LIPID MAPS -a fatty acid database was performed. The selected protein-ligand complexes were subjected to molecular dynamics simulation (MDs). The Binding Free Energy of complexes was predicted using MM/PBSA. Further, the drug-likeness and pharmacokinetic properties of ligands were also analyzed. Out of 46,200 FAs scrutinized virtually against the three protein targets (viz., GtfC, Ag I/II and srtA), top 5 FAs for each protein were identified as the best hit based on interaction energies viz., hydrogen bond numbers and hydrophobic interaction. Further, two common FAs (LMFA01050418 and LMFA01040045) that showed high binding affinity against Ag I/II and srtA were selected for MDs analysis. A 100ns MDs unveiled a stable conformation. Results of Rg signified that FAs does not induce significant structural & conformational changes. SASA indicated that the complexes maintain higher thermodynamic stability during MDs. The predicted binding free energy (MM/PBSA) of complexes elucidated their stable binding interaction. ADME analysis suggested the FAs are biologically feasible as therapeutic candidates. Overall, the presented in silico data is the first of its kind in delineating FAs as promising anticaries agents of future.Communicated by Ramaswamy H. Sarma.

Combination of bendamustine-azacitidine against Syk target of breast cancer: an in silico study.

Breast cancer (BC) is the most serious and second leading cause of death in women worldwide. When breast cancer is diagnosed and treated early, the chance of long-term survival is up to 90%. On the other hand, 90% of BC patient deaths are due to metastasis and a lack of effective early diagnosis. The existing conventional chemotherapy provides negative feedback due to transportation barriers towards the action sites, multidrug resistance, poor bio-availability, non-specific delivery and systemic side effects on the healthy tissue. Syk protein Kinase has been reported in BC, as a tumor modulator, providing a pro-survival signal and also by restricting epithelial-mesenchymal transition, enhancing cell-cell interactions and inhibiting migration. In the present study, we explored the possibility of targeting BC by attenuating Syk protein Kinase. Hence, we have conjugated the hydrophobic Bendamustine (BEN) and hydrophilic Azacitidine (AZA) anticancer drugs to evaluate their efficacy against BC. The native drugs (BEN and AZA) and designed drug-drug conjugate (BEN-AZA) were docked with Syk protein. Then, the docked complex was performed for Binding Free Energy and Molecular Dynamics Simulations. Furthermore, DFT and ADME properties were carried out. The results revealed that the designed drug-drug conjugate has a better docking score, ΔGbind and admirable stability throughout the simulation when compared with native drugs. In DFT and ADME analyses, the designed drug-drug conjugate has shown good stereo electronic features and pharmaceutical relevant parameters than that of native drugs. The overall results suggested that the designed drug-drug conjugate may be a suitable candidate for BC treatment.Communicated by Ramaswamy H. Sarma.

In silico approach of naringin as potent phosphatase and tensin homolog (PTEN) protein agonist against prostate cancer.

Prostate cancer (PC) is one of the major impediments affecting men, which leads approximately 31,620 deaths in both developing and developed countries. Although some chemotherapy drugs have been reported for prostate cancer, they are not effective due to the lack of safety, efficacy and low selectivity. Hence, the novel alternative anticancer agents with remarkable effect are highly appreciable. Natural plants contain several bio-active compounds which have been traditionally used for the various medical treatments. Particularly, naringin is a natural bio-active compound commonly found in the citrus fruits, which have shown numerous biological activities. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, which activates both lipid phosphates and protein phosphates. The PTEN gene is negative regulator of PI3K/AKT/mTOR pathways, since, this signaling pathway play an essential role in the cell survival, proliferation and migration. In the present in silico investigation, structure based virtual screening, molecular docking, molecular dynamics simulation and Adsorption, Distribution, Metabolism, Excretion (ADME) prediction were employed to determine the binding affinity, stability and drug likeness properties of top ranked screened compounds and naringin, respectively. The results revealed that the complex has good molecular interactions, binding stability (peak between 0.3 and 0.4 nm) and no violations in the Lipinski Rule of 5 in naringin, but the screened compounds violated the drug likeness properties. From the in silico analyses, it is identified that naringin compound might assist in the development of novel therapeutic candidate against prostate cancer. Communicated by Ramaswamy H. Sarma.

Indian Ethnomedicinal Phytochemicals as Promising Inhibitors of RNA-Binding Domain of SARS-CoV-2 Nucleocapsid Phosphoprotein: An In Silico Study.

SARS-CoV-2, an etiological agent of COVID-19, has been the reason for the unexpected global pandemic, causing severe mortality and imposing devastative effects on public health. Despite extensive research work put forward by scientist around globe, so far, no suitable drug or vaccine (safe, affordable, and efficacious) has been identified to treat SARS-CoV-2. As an alternative way of improvising the COVID-19 treatment strategy, that is, strengthening of host immune system, a great deal of attention has been given to phytocompounds from medicinal herbs worldwide. In a similar fashion, the present study deliberately focuses on the phytochemicals of three Indian herbal medicinal plants viz., Mentha arvensis, Coriandrum sativum, and Ocimum sanctum for their efficacy to target well-recognized viral receptor protein through molecular docking and dynamic analyses. Nucleocapsid phosphoprotein (N) of SARS-CoV-2, being a pivotal player in replication, transcription, and viral genome assembly, has been recognized as one of the most attractive viral receptor protein targets for controlling the viral multiplication in the host. Out of 127 phytochemicals screened, nine (linarin, eudesmol, cadinene, geranyl acetate, alpha-thujene, germacrene A, kaempferol-3-O-glucuronide, kaempferide, and baicalin) were found to be phenomenal in terms of exhibiting high binding affinity toward the catalytic pocket of target N-protein. Further, the ADMET prediction analysis unveiled the non-tumorigenic, noncarcinogenic, nontoxic, non-mutagenic, and nonreproductive nature of the identified bioactive molecules. Furthermore, the data of molecular dynamic simulation validated the conformational and dynamic stability of the docked complexes. Concomitantly, the data of the present study validated the anti-COVID efficacy of the bioactives from selected medicinal plants of Indian origin.

Emerging Therapeutic Approaches to Combat COVID-19: Present Status and Future Perspectives.

Coronavirus disease (COVID-19) has emerged as a fast-paced epidemic in late 2019 which is disrupting life-saving immunization services. SARS-CoV-2 is a highly transmissible virus and an infectious disease that has caused fear among people across the world. The worldwide emergence and rapid expansion of SARS-CoV-2 emphasizes the need for exploring innovative therapeutic approaches to combat SARS-CoV-2. The efficacy of some antiviral drugs such as remdesivir, favipiravir, umifenovir, etc., are still tested against SARS-CoV-2. Additionally, there is a large global effort to develop vaccines for the protection against COVID-19. Because vaccines seem the best solution to control the pandemic but time is required for its development, pre-clinical/clinical trials, approval from FDA and scale-up. The nano-based approach is another promising approach to combat COVID-19 owing to unique physicochemical properties of nanomaterials. Peptide based vaccines emerged as promising vaccine candidates for SARS-CoV-2. The study emphasizes the current therapeutic approaches against SARS-CoV-2 and some of the potential candidates for SARS-CoV-2 treatment which are still under clinical studies for their effectiveness against SARS-CoV-2. Overall, it is of high importance to mention that clinical trials are necessary for confirming promising drug candidates and effective vaccines and the safety profile of the new components must be evaluated before translation of in vitro studies for implementation in clinical use.

Promising phytochemicals of traditional Indian herbal steam inhalation therapy to combat COVID-19 - An in silico study.

BACKGROUND: COVID-19, the presently prevailing global public health emergency has culminated in international instability in economy. This unprecedented pandemic outbreak pressingly necessitated the trans-disciplinary approach in developing novel/new anti-COVID-19 drugs especially, small molecule inhibitors targeting the seminal proteins of viral etiological agent, SARS-CoV-2. METHODS: Based on the traditional medicinal knowledge, we made an attempt through molecular docking analysis to explore the phytochemical constituents of three most commonly used Indian herbs in 'steam inhalation therapy' against well recognized viral receptor proteins. RESULTS: A total of 57 phytochemicals were scrutinized virtually against four structural protein targets of SARS-CoV-2 viz. 3CLpro, ACE-2, spike glycoprotein and RdRp. Providentially, two bioactives from each of the three plants i.e. apigenin-o-7-glucuronide and ellagic acid from Eucalyptus globulus; eudesmol and viridiflorene from Vitex negundo and; vasicolinone and anisotine from Justicia adhatoda were identified to be the best hit lead molecules based on interaction energies, conventional hydrogen bonding numbers and other non-covalent interactions. On comparison with the known SARS-CoV-2 protease inhibitor -lopinavir and RdRp inhibitor -remdesivir, apigenin-o-7-glucuronide was found to be a phenomenal inhibitor of both protease and polymerase, as it strongly interacts with their active sites and exhibited remarkably high binding affinity. Furthermore, in silico drug-likeness and ADMET prediction analyses clearly evidenced the usability of the identified bioactives to develop as drug against COVID-19. CONCLUSION: Overall, the data of the present study exemplifies that the phytochemicals from selected traditional herbs having significance in steam inhalation therapy would be promising in combating COVID-19.

Phyto-Engineered Gold Nanoparticles (AuNPs) with Potential Antibacterial, Antioxidant, and Wound Healing Activities Under in vitro and in vivo Conditions.

BACKGROUND: A diabetic ulcer is one of the major causes of illness among diabetic patients that involves severe and intractable complications associated with diabetic wounds. Hence, a suitable wound-healing agent is urgently needed at this juncture. Greener nanotechnology is a very promising and emerging technology currently employed for the development of alternative medicines. Plant-mediated synthesis of metal nanoparticles has been intensively investigated and regarded as an alternative strategy for overcoming various diseases and their secondary complications like microbial infections. Hence, we are interested in developing phyto-engineered gold nanoparticles as useful therapeutic agents for the treatment of infectious diseases and wounds effectively. METHODS AND RESULTS: We have synthesized phyto-engineered gold nanoparticles from the aqueous extract of Acalypha indica and characterized using advanced bio-analytical techniques. The surface plasmon resonance feature and crystalline behavior of gold nanoparticles were revealed by ultraviolet-visible spectroscopy and X-ray diffraction, respectively. High-performance liquid chromatography analysis of the extract demonstrated the presence of different constituents, while major functional groups were interpreted by the Fourier-transform infrared spectroscopy as the various stretching vibrations appeared for important O-H (3443 cm-1), C=O (1644 cm-1) and C-O (1395 cm-1) groups. Scanning electron microscopy, high-resolution transmission electron microscopy results revealed a distribution of spherical and rod-like nanostructures with 20 nm of size. The gold nanoparticle-coated cotton fabric was evaluated for the antibacterial activity against Staphylococcus epidermidis and Escherichia coli bacterial strains which revealed remarkable inhibition at the zone of inhibition of 31 mm diameter against S. epidermidis. Further, antioxidant activity was tested for their free radical scavenging property, and the maximum antioxidant activity of the extract containing gold nanoparticles was found to be 80% at 100 µg/mL. The potent free radical scavenging property of the nanoparticles is observed at IC50 value 16.25 µg/mL. Moreover, in vivo wound-healing activity was carried out using BALB/c mice model with infected diabetic wounds and observed the stained microscopic images at different time intervals (day 2, day 7 and day 15). It was noted that in 15 days, the wound area is completely re-epithelialized due to the presence of different morphologies such as spherical, needle and triangle nanoparticles. The re-epithelialization layer is fully covered by nanoparticles on the wound area and also collagen filled in the scar tissue when compared with the control group. CONCLUSION: The pharmacological evaluation results of the study indicated an encouraging antibacterial and antioxidant activity of the greener synthesized gold nanoparticles tethered with aqueous extract of Acalypha indica. Moreover, we demonstrated enhanced in vivo wound-healing efficiency of the synthesized gold nanoparticles through the animal model. Thus, the outcome of this work revealed that the phyto-engineered gold nanoparticles could be useful for biomedical applications, especially in the development of promising antibacterial and wound-healing agents.

Synthesis, characterization and antibacterial activity of polyaniline/Pt-Pd nanocomposite.

Pt colloid and Pt-Pd colloid, pristine polyaniline, polyaniline/Pt nanocomposite and polyaniline/Pt-Pd nanocomposite were synthesized by simple chemical method. They were characterized by UV-Vis, FT-IR, XRD, TGA, SEM, HR-SEM and HR-TEM with EDAX techniques. The results proved that there is a strong interaction between metal nanoparticles (Pt-Pd) and polyaniline chains. This interaction creates changes in the backbone chain of polyaniline/Pt-Pd nanocomposite when compared to pristine polyaniline. The synthesized materials were evaluated for antibacterial activity, minimal inhibitory concentration and minimal bactericidal concentration. The results indicated that the nanocomposites exhibited improved antibacterial activity when compared to pristine polyaniline and individual metal colloids. This is the first report on the chemical synthesis of polyaniline/Pt-Pd nanocomposite, which exhibits antibacterial activity at micro molar concentration levels.

Synthesis and characterization of polyaniline/Ag-Pt nanocomposite for improved antibacterial activity.

Polyaniline, polyaniline/Ag-Pt nanocomposite and bimetal (Ag-Pt) colloidal solution were chemically synthesized and characterized by UV-vis, XRD, FT-IR, TGA, HRSEM with EDAX and HRTEM techniques. The results reveal that there was a strong interaction between Ag-Pt nanocomposite and polyaniline chains. This interaction makes only small changes in the backbone chain of polyaniline/Ag-Pt nanocomposite when compared with polyaniline. TGA result revealed greater thermal stability of the composite. HRSEM images showed pebble like morphology for polyaniline/Ag-Pt nanocomposite. The average grain size of Ag-Pt nanoparticle was found to be 2-5 nm, which is confirmed by HRTEM analysis. The polyaniline and polyaniline/Ag-Pt nanocomposite were tested for antibacterial activity. The composite showed improved inhibition efficiency with a maximum zone diameter of 30 ± 1.25 mm against Staphylococcus aureus. This is the first report on the synthesis and its antibacterial activity of polyaniline/Ag-Pt nanocomposite.