A series of novel 1,5-diaryl pyrazole derivatives targeting the COX enzyme were designed by combined ligand and structure-based approach. The designed molecules were then further subjected to ADMET and molecular docking studies. Out of 34 designed compounds, the top-10 molecules from the computation studies were synthesized, characterized, and evaluated for COX-2 inhibition and anti-cancer activity. Initially, the target compounds were screened for the protein denaturation assay. The results of the top-five molecules T2, T3, T5, T6, and T9 were further subjected to in vitro COX-2 enzymatic assay and anti-cancer activity. As far as COX-2 inhibitory activity is considered, two compounds, T3 and T5, exhibited the half maximum inhibitory concentration (IC₅₀) at 0.781 µM and 0.781 µM respectively. Further, the two compounds T3 and T5, when evaluated for COX-1 inhibition, exhibited excellent inhibitory activity with T3 IC₅₀ of 4.655μM and T5 with IC₅₀ of 5.596 μM. The compound T5 showed more significant human COX-2 inhibition, with a selectivity index of 7.16, when compared with T3, which had a selectivity index of 5.96. Further, in vitro anti-cancer activity was screened against two cancer cell lines in which compounds T2 and T3 were active against A549 cell lines and T6 was active against the HepG2 cell line. Stronger binding energy was found by comparing MM-PBSA simulations with molecular docking, which suggests that compounds T3 and T5 have a better possibility of being effective compounds, in which T5 showed higher binding affinity. The results suggest that these compounds have the potential to develop effective COX-2 inhibitors as anti-cancer agents.

The recalcitrant spread of the COVID-19 pandemic produced by the novel coronavirus SARS-CoV-2 is one of the most destructive occurrences in history. Despite the availability of several effective vaccinations and their widespread use, this line of immunization often faces questions about its long-term efficacy. Since coronaviruses rapidly change, and multiple SARS-CoV-2 variants have emerged around the world. Therefore, finding a new target-based medication became a priority to prevent and control COVID-19 infections. The main protease (Mpro) is a salient enzyme in coronaviruses that plays a vital role in viral replication, making it a fascinating therapeutic target for SARS-CoV-2. We screened 0.2 million natural products against the Mpro of SARS-CoV-2 using the Universal Natural Product Database (UNPD). As well, we studied the role of ionic liquids (ILs) on the structural stabilization of Mpro. Cholinium-based ILs are biocompatible and used for a variety of biomedical applications. Molecular docking was employed for the initial screening of natural products and ILs against Mpro. To predict the drug-likeness features of lead compounds, we calculated the ADMET properties. We performed MD simulations for the selected complexes based on the docking outcomes. Using MM/PBSA approaches, we conclude that compounds NP-Hit2 (−25.6 kcal mol⁻¹) and NP-Hit3 (−25.3 kcal mol⁻¹) show stronger binding affinity with Mpro. The hotspot residues of Thr25, Leu27, His41, Met49, Cys145, Met165, and Gln189 strongly interacted with the natural compounds. Furthermore, naproxenate, ketoprofenate, and geranate, cholinium-based ILs strongly interact with Mpro and these ILs have antimicrobial properties. Our findings will aid in the development of effective Mpro inhibitors.

Triple-negative breast cancer (TNBC) is the most aggressive kind of breast cancer known to mankind. It is a heterogeneous disease that is formed due to the missing estrogen, progesterone and human epidermal growth factor 2 receptors. Poly(ADP-ribose) polymerase-1 (PARP-1) protein helps in the development of TNBC by repairing the cancer cells, which proliferate and spread metastatically. To determine the potential PARP-1 inhibitors (PARPi), 0.2 million natural products from Universal Natural Product Database were screened using molecular docking and six hit compounds were selected based on their binding affinity towards PARP-1. The bio-availability and drug-like properties of these natural products were evaluated using ADMET analysis. Molecular dynamics simulations were conducted for these complexes for 200 ns to examine their structural stability and dynamic behaviour and further compared with the complex of talazoparib (TALA), an FDA-approved PARPi. Using MM/PBSA calculations, we conclude that the complexes HIT-3 and HIT-5 (−25.64 and −23.14 kcal/mol, respectively) show stronger binding energies with PARP-1 than TALA with PARP-1 (−10.74 kcal/mol). Strong interactions were observed between the compounds and hotspot residues, Asp770, Ala880, Tyr889, Tyr896, Ala898, Asp899 and Tyr907, of PARP-1 due to the existence of various types of non-covalent interactions between the compounds and PARP-1. This research offers critical information about PARPi, which could potentially be incorporated into the treatment of TNBC. Moreover, these findings were validated by comparing them with an FDA-approved PARPi.

Alzheimer's disease (AD) is a neurological condition that worsens over time and causes linguistic difficulties, cognitive decline, and memory loss. Since AD is a complicated, multifaceted illness, it is critical to identify drugs to combat this degenerative condition. Histone deacetylase 2 (HDAC2) represents a promising epigenetic target for neurodegenerative diseases. So, for this study, we chose HDAC2 as the targeted protein. Repurposing drugs has many advantages, including reduced costs and high profits. There is a lower probability of malfunction because the unique drug candidate has previously completed numerous investigations. In this study, we have taken 58 clinically approved food and drug administration (FDA) drugs utilized in clinical trials for AD. Molecular docking was carried out for the 58 compounds. The telmisartan drug has the highest binding score of −9.4 kcal mol⁻¹. The angiotensin II receptor blocker (ARB) telmisartan has demonstrated some promise in AD research as of the last update in January 2022. However, its exact significance in treating or preventing AD is still being studied. Molecular dynamics (MD) and molecular mechanics with generalized born and surface area solvation (MM-GBSA)/interaction entropy (IE) calculations were carried out to study the structural stability of the complexes. Umbrella sampling (US) techniques are a cutting-edge drug development method to understand more about the interactions between protein and ligand. π–π stacking interactions play a major role in helping the ligand to bind in the zinc bounding domain of the protein. From these analyses, we conclude that telmisartan, which is a cardiovascular drug, is more potent than the other drugs to treat AD. The anti-inflammatory, neuroprotective, and blood-brain barrier-crossing qualities of telmisartan make it a promising therapeutic agent for AD; however, more research, including larger clinical trials, is needed to determine the drug's precise role in treating AD.

Biocompatible cholinium-based ionic liquids (ILs) are used extensively in the pharmaceutical and biomedical industries. To enhance structural stability and solubility of drugs, as well as their controlled delivery, IL-based active pharmaceutical ingredients (API) are used widely. In this study, we selected two different sets of biodegradable ILs which also have a direct influence on the structure and stability of insulin. Moreover, we used DFT-based electronic structure calculations with molecular dynamics (MD) simulations to study the effect of a mixture of two different anions in the IL medium and the role of water molecules on the stability of insulin. Microhydration and molecular-level DFT calculations suggest that ILs based on choline geranate [Cho][Ger] and choline taurine [Cho][Tau] differ in their hydration patterns, and thus the stability of the clusters varies significantly. This finding is important for exploring the role of water molecules within these mixtures (i.e., on the interactions between [Ger] and [Tau]). From our calculations it is found that the [Cho][Ger] IL stabilizes the insulin dimer structure strongly through water-mediated H-bonding interactions, whereas the [Cho][Ger][Tau] ternary complex destabilizes insulin. This indicates that IL mixtures over a wide range of concentrations and water molecules at the interface may influence the structural stability and enable suitable combinations of oral formulations to be predicted for drug-delivery applications. From the MD simulations, we conclude that [Cho][Ger] stabilizes the insulin dimer. Our combined DFT and MD simulations will provide valuable information for experimentalists to design and develop novel oral insulin formulations.

A class I histone deacetylase HDAC8 is associated with several diseases, including cancer, intellectual impairment and parasite infection. Most of the HDAC inhibitors that have so far been found to inhibit HDAC8 limit their efficacy in the clinic by producing toxicities. It is therefore very desirable to develop specific HDAC8 inhibitors. The emergence of HDAC inhibitors derived from natural sources has become quite popular. In recent decades, it has been shown that naturally occurring HDAC inhibitors have strong anticancer properties. A total of 0.2 million natural compounds were screened against HDAC8 from the Universal Natural Product Database (UNPD). Molecular docking was performed for these natural compounds and the top six hits were obtained. In addition, molecular dynamics (MD) simulations were used to evaluate the structural stability and binding affinity of the inhibitors, which showed that the protein–ligand complexes remained stable throughout the 100 ns simulation. MM-PBSA method demonstrated that the selected compounds have high affinity towards HDAC8. We infer from our findings that Hit-1 (−29.35 kcal mol⁻¹), Hit-2 (−29.15 kcal mol⁻¹) and Hit-6 (−30.28 kcal mol⁻¹) have better binding affinity and adhesion to ADMET (absorption, distribution, metabolism, excretion and toxicity) characteristics against HDAC8. To compare our discussions and result in an effective way. We performed molecular docking, MD and MM-PBSA analysis for the FDA-approved drug romidepsin. The above results show that our hits show better binding affinity than the compound romidepsin (−12.03 ± 4.66 kcal mol⁻¹). The important hotspot residues Asp29, Ile34, Trp141, Phe152, Asp267, Met274 and Tyr306 have significantly contributed to the protein–ligand interaction. These findings suggest that in vitro testing and additional optimization may lead to the development of HDAC8 inhibitors. Communicated by Ramaswamy H. Sarma