Design, Virtual Screening, Molecular Docking, ADME and Cytotoxicity Studies of 1,3,5-Triazine Containing Heterocyclic Scaffolds as Selective BRAF Monomeric, Homo and Heterodimeric Inhibitors.

BACKGROUND: v-RAF murine sarcoma viral homolog B1 (BRAF) is one of the most frequently mutated kinases in human cancers. BRAF exhibits three classes of mutations: Class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). METHOD: In this manuscript, the protein-ligand interaction site of all three mutants: BRAF monomer, BRAF homodimer BRAF2:14-3-32, and BRAF heterodimer BRAF:14-3-32:MEK (Mitogen extracellular Kinase) has been discussed. FDA-approved drugs still have limitations against all three classes of mutants, especially against the second and third classes. Using the DesPot grid model, 1114 new compounds were designed. Using virtual screening, the three PDB Ids 4XV2 for monomers, 7MFF for homodimers, and 4MNE for heterodimers were used for 1114 newly designed compounds. RESULT: Dabrafenib, encorafenib, sorafenib and vemurafenib were included as standard drugs. The top 10 hit molecules were identified for each protein. Additional binding studies were performed using molecular docking studies on the protein-ligand site of each PDB identifier. Absorption, distribution, metabolism, excretion (ADME) and toxicity studies were also performed. CONCLUSION: It was identified that top-hit molecules had better binding and interaction activity than standard in all three classes of mutants.

MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives.

MEK1/2 are critical components of the RAS-RAF-MEK-ERK or MAPK signalling pathway that regulates a variety of cellular functions including proliferation, survival, and differentiation. In 1997, a lung cancer cell line was first found to have a MEK mutation (encoding MEK2P298L). MEK is involved in various human cancers such as non-small cell lung cancer (NSCLC), spurious melanoma, and pancreatic, colorectal, basal, breast, and liver cancer. To date, 4 MEK inhibitors i.e., trametinib, cobimetinib, selumetinib, and binimetinib have been approved by the FDA and several are under clinical trials. In this review, we have highlighted structural insights into the MEK1/2 proteins, such as the αC-helix, catalytic loop, P-loop, F-helix, hydrophobic pocket, and DFG motif. We have also discussed current issues with all FDA-approved MEK inhibitors or drugs under clinical trials and combination therapies to improve the efficacy of clinical drugs. Finally, this study addressed recent developments on synthetic MEK inhibitors (from their discovery in 1997 to 2022), their unique properties, and their relevance to MEK mutant inhibition.

Design, one-pot synthesis, computational and biological evaluation of diaryl benzimidazole derivatives as MEK inhibitors.

MEK mutations are more common in various human malignancies, such as pancreatic cancer (70-90%), mock melanoma (50%), liver cancer (20-40%), colorectal cancer (25-35%), melanoma (15-20%), non-small cell lung cancer (10-20%) and basal breast cancer (1-5%). Considering the significance of MEK mutations in diverse cancer types, the rational design of the proposed compounds relies on the structural resemblance to FDA-approved MEK inhibitors like selumetinib and binimetinib. The compound under design features distinct substitutions at the benzimidazole moiety, specifically at positions 2 and 3, akin to the FDA-approved drugs, albeit differing in positions 5 and 6. Subsequent structural refinement was guided by key elements including the DFG motif, hydrophobic pocket and catalytic loop of the MEK protein. A set of 15 diverse diaryl benzimidazole derivatives (S1-S15) were synthesized via a one-pot approach and characterized through spectroscopic techniques, including MASS, IR, 1H NMR and 13C NMR. In vitro anticancer activities of all the synthesized compounds were evaluated against four cancer cell lines, A375, HT -29, A431 and HFF, along with the standard drug trametinib. Molecular docking was performed for all synthesized compounds (S1-15), followed by 950 ns molecular dynamics simulation studies for the promising compounds S1, S5 and S15. The stability of these complexes was assessed by calculating the root-mean-square deviation, solvent accessible surface area and gyration radius relative to their parent structures. Additionally, free energy of binding calculations were performed. Based on the biological and computational results, S15 was the most potent compound and S1 and S5 are comparable to the standard drug trametinib.Communicated by Ramaswamy H. Sarma.

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022.

Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.

Green Synthesis of Genistein-Fortified Zinc Ferrite Nanoparticles as a Potent Hepatic Cancer Inhibitor: Validation through Experimental and Computational Studies.

In hepatic cancer, precancerous nodules account for damage and inflammation in liver cells. Studies have proved that phyto-compounds based on biosynthetic metallic nanoparticles display superior action against hepatic tumors. This study targeted the synthesis of genistein-fortified zinc ferrite nanoparticles (GENP) trailed by anticancer activity assessment against diethylnitrosamine and N-acetyl-2-aminofluorene induced hepatic cancer. The process of nucleation was confirmed by UV/VIS spectrophotometry, X-ray beam diffraction, field-emission scanning electron microscopy, and FT-IR. An in vitro antioxidant assay illustrated that the leaves of Pterocarpus mildbraedii have strong tendency as a reductant and, in the nanoformulation synthesis, as a natural capping agent. A MTT assay confirmed that GENP have a strong selective cytotoxic potential against HepG2 cancer cells. In silico studies of genistein exemplified the binding tendency towards human matrix metalloproteinase comparative to the standard drug marimastat. An in vivo anticancer evaluation showed that GENP effectively inhibit the growth of hepatic cancer by interfering with hepatic and non-hepatic biochemical markers.

Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective.

Cancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop safer and target-specific anticancer drugs. More than 85% of all physiologically active pharmaceuticals are heterocycles or contain at least one heteroatom. Nitrogen heterocycles constituting the most common heterocyclic framework. In this study, we have compiled the FDA approved heterocyclic drugs with nitrogen atoms and their pharmacological properties. Moreover, we have reported nitrogen containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, ß-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines, which are used in the treatment of different types of cancer, concurrently covering the biochemical mechanisms of action and cellular targets.

Virtual screening, structure based pharmacophore mapping, and molecular simulation studies of pyrido[2,3-d]pyrimidines as selective thymidylate synthase inhibitors.

Human thymidylate synthase is the rate-limiting enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate. dUMP (pyrimidine) and folate binding site hTS inhibitors showed resistance in colorectal cancer (CRC). In the present study, we have performed virtual screening of the pyrido[2,3-d]pyrimidine database, followed by binding free energy calculations, and pharmacophore mapping to design novel pyrido[2,3-d]pyrimidine derivatives to stabilize inactive confirmation of hTS. A library of 42 molecules was designed. Based on the molecular docking studies, four ligands (T36, T39, T40, and T13) were identified to have better interactions and docking scores with the catalytic sites [dUMP (pyrimidine) and folate binding sites] of hTS protein than standard drug, raltitrexed. To validate efficacy of the designed molecules, we performed molecular dynamics simulation studies at 1000 ns with principal component analysis and binding free energy calculations on the hTS protein, also drug likeness properties of all hits were in acceptable range. Compounds T36, T39, T40, and T13 interacted with the catalytic amino acid (Cys195), an essential amino acid for anticancer activity. The designed molecules stabilized the inactive conformation of hTS, resulting in the inhibition of hTS. The designed compounds will undergo synthesis and biological evaluation, which may yield selective, less toxic, and highly potent hTS inhibitors.Communicated by Ramaswamy H. Sarma.

A review on medicinally important heterocyclic compounds and importance of biophysical approach of underlying the insight mechanism in biological environment.

Heterocyclic derivatives have more interesting biological properties which hold a remarkable place in pharmaceutical industries due to their unique physiochemical properties and ease of adaption in various biological environments. Of many, the above-said derivatives have been recently examined for their promising action against a few malignancies. Specifically, anti-cancer research has benefited from these derivatives' natural flexibility and dynamic core scaffold. In any case, concerning some other promising anti-cancer drugs, heterocyclic derivative doesn't come without deficiencies. To be a successful drug candidate it should poses Absorption, Distribution, Metabolism and Eliminations (ADME) parameter, and must also have good binding interaction towards carrier protein as well as DNA and less in toxic nature, economically feasible. In this review, we described the overview of biologically important heterocyclic derivatives and their main application in medicine. Further, we focus types of biophysical techniques to understand the binding interaction mechanism.Communicated by Ramaswamy H. Sarma.

Metal Complexes in Cancer Treatment: Journey So Far.

Metal complexes in cancer therapy have attracted much interest mainly because metals exhibit unique characteristics, such as redox activity, metal-ligand interaction, structure and bonding, Lewis acid properties etc. In 1965, Barnett Rosenberg serendipitously discovered the metal-based compound cisplatin, an outstanding breakthrough in the history of metal-based anticancer complexes and led to a new area of anticancer drug discovery. Many metal-based compounds have been studied for their potential anticancer properties. Some of these compounds have FDA approval for clinical use, while others are now undergoing clinical trials for cancer therapy and detection. In the present study, we have highlighted the primary mode of action of metallic complexes and all FDA-approved/under clinical trial drugs with reference to cancer treatment. This review also focuses on recent progress on metal-based complexes such as platinum, ruthenium, iron, etc. with potential anticancer activities.

Design, synthesis, and in silico study of hybrid oxoazetidine conjugated thiazoles as anti-EGFR with cytotoxicity activity.

We report a series of hybrid oxoazetidine conjugated thiazoles as epidermal growth factor receptor (EGFR) inhibitors, which were synthesized and tested using a variety of in silico and in vitro studies. The compounds were found to be active against breast and hepatic cancer cell lines, with Compounds 7a, 7b, and 7e being the most potent ones. The derivatives were also evaluated for molecular docking and complementarity studies to explicate fundamental substituent groups essential for their bioactivity. Moreover, the structural activity relationship of the analogues was performed for future compound optimization. These studies advocated that the analogues have a high affinity towards EGFR with favorable anticancer potential. The study advised that the derivatives have potency against breast and hepatic cancer and can assist as an initial scaffold for further development of anti-EGFR compounds.

Computational and experimental therapeutic efficacy analysis of andrographolide phospholipid complex self-assembled nanoparticles against Neuro2a cells.

BACKGROUND: Neuroblastoma is one of the most common malignancies in childhood, accounts for approximately 7% of all malignancies. Andrographolide (AN) inhibits cancer cells progression via multiple pathways like cell cycle arrest, mitochondrial apoptosis, NF-κß inhibition, and antiangiogenesis mechanism. Despite multiple advantages, application of AN is very limited due to its low aqueous solubility (6.39 ± 0.47 µg/mL), high lipophilicity (log P âˆ¼ 2.632 ± 0.135), and reduced stability owing to pH sensitive lactone ring. OBJECTIVES AND RESULTS: In present investigation, a molecular complex of AN with soya-L-α-phosphatidyl choline (SPC) was synthesized as ANSPC and characterized by FT-IR and1H NMR spectroscopy. Spectral and molecular simulation techniques confirmed the intermolecular interactions between the 14-OH group of AN and the N+(CH3)3part of SPC. In addition, molecular dynamics (MD) simulation was used to determine the degree of interaction between various proteins such as TNF-α, caspase-3, and Bcl-2. Later, ANSPC complex was transformed in to self-assembled soft nanoparticles of size 201.8 ± 1.48 nm with PDI of 0.092 ± 0.004 and zeta potential of -21.7 ± 0.85 mV. The IC50 offree AN (8.319 µg/mL) and the self-assembled soft ANSPC nanoparticles (3.406 µg/mL âˆ¼ 1.2 µg of AN) against Neuro2a cells was estimated with significant (P < 0.05) difference. Interestingly, the self-assembled soft ANSPC nanoparticles showed better endocytosis compared to free AN in Neuro2a cells. In-vitrobiological assays confirmed that self-assembled soft ANSPC nanoparticles induces apoptosis in Neuro2a cells by declining the MMP (Δψm) and increasing the ROS generation. CONCLUSION: Self-assembled soft ANSPC nanoparticles warrant further in-depth antitumor study in xenograft model of neuroblastoma to establish the anticancer potential.

Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAFV600E inhibitors.

The "RAS-RAF-MEK-ERK" pathway is an important signaling pathway in melanoma. BRAFV600E (70-90%) is the most common mutation in this pathway. BRAF inhibitors have four types of conformers: type I (αC-IN/DFG-IN), type II (αC-IN/DFG-OUT), type I1/2 (αC-OUT/DFG-IN), and type I/II (αC-OUT/DFG-OUT). First- and second-generation BRAF inhibitors show resistance to BRAFV600E and are ineffective against malignancies induced by dimer BRAF mutants causing 'paradoxical' activation. In the present study, we performed molecular modeling of pyrimidine-sulfonamide hybrids inhibitors using 3D-QSAR, molecular docking, and molecular dynamics simulations. Previous reports reveal the importance of pyrimidine and sulfonamide moieties in the development of BRAFV600E inhibitors. Analysis of 3D-QSAR models provided novel pyrimidine sulfonamide hybrid BRAFV600E inhibitors. The designed compounds share similarities with several structural moieties present in first- and second-generation BRAF inhibitors. A total library of 88 designed compounds was generated and molecular docking studies were performed with them. Four molecules (T109, T183, T160, and T126) were identified as hits and selected for detailed studies. Molecular dynamics simulations were performed at 900 ns and binding was calculated. Based on molecular docking and simulation studies, it was found that the designed compounds have better interactions with the core active site [the nucleotide (ADP or ATP) binding site, DFG motif, and the phospho-acceptor site (activation segment) of BRAFV600E protein than previous inhibitors. Similar to the FDA-approved BRAFV600E inhibitors the developed compounds have [αC-OUT/DFG-IN] conformation. Compounds T126, T160 and T183 interacted with DIF (Leu505), making them potentially useful against BRAFV600E resistance and malignancies induced by dimer BRAF mutants. The synthesis and biological evaluation of the designed molecules is in progress, which may lead to some potent BRAFV600E selective inhibitors.

Guava Leaf Essential Oil as a Potent Antioxidant and Anticancer Agent: Validated through Experimental and Computational Study.

Several drugs now employed in cancer therapy were discovered as a result of anticancer drug research based on natural products. Here, we reported the in vitro antioxidant and anticancer activity followed by in silico anticancer and estrogen-like activity of Psidium guajava L. essential oil against ER-α receptors which lead to potential inhibitory action against breast cancer pathways. METHODS: The bioactive compounds in guava essential oil were screened using gas chromatography-mass spectrometry (GC-MS). Similarly, the antioxidant properties of the extracted oil were evaluated using 2,2-Diphenyl-1-picrylhydrazyl scavenging assay. Furthermore, the in vitro anticancer activity of guava oil was observed through the MTT assay and an in silico molecular docking experiment was also carried out to ensure that they fit into the estrogen receptors (ERs) and possess anticancer potential. RESULTS: The GC-MS profile of the essential oil revealed the presence of 17 chemicals, with limonene (51.3%), eucalyptol (21.3%), caryophyllene oxide (6.2%), caryophyllene (5.6%), and nerolidol (4.5%) occupying more than one-third of the chromatographic spectrum zone. Guava leaves' essential oil (EO) inhibited DPPH (2,2-diphenyl-1-picrylhydrazyl) radicals and exhibited concentration dependent free radical scavenging activity, acting as a potent antioxidant with an IC50 value of 29.3 ± 0.67 µg/mL. The outcome of the MTT assay showed that the extracted guava oil had nearly the same efficacy against breast and liver cancer cells at a low concentration (1 µg/mL), giving 98.3 ± 0.3% and 98.5 ± 0.4% cell viability against HepG2 at 1 µg/mL, respectively. When the concentration of essential oil was increased, it showed a small reduction in the percentage of viable cells. While conducting an in silico study of all the screened compounds, the potential for hydroxycaryophyllene, caryophyllene, caryophyllene oxide, humulene, terpineol, and calamenene to inhibit tumor growth was bolstered due to a resemblance to 4-hydroxytamoxifen, thereby implying that these compounds may act as selective estrogen receptor modulators (SERMs). The ADME analysis of the compounds indicated above revealed that they exhibit excellent drug likeness properties and follow the Lipinski rule of five. CONCLUSIONS: Consequently, they have a substantial anticancer therapeutic potential and can be used for novel drug discovery in the effort to minimize the global burden of breast cancer.

A systems biology investigation of curcumin potency against TGF-ß-induced EMT signaling in lung cancer.

Curcumin (diferuloylmethane) is bioactive phenolic compound which exerts diverse antimetastatic effect. Several studies have reported the antimetastatic effect of curcumin by its ability to modulate the epithelial-to-mesenchymal transition (EMT) process in different cancers, but underlying molecular mechanism is poorly understood. EMT is a highly conserved biological process in which epithelial cells acquire mesenchymal-like characteristics by losing their cell-cell junctions and polarity. As a consequence, deviation in cellular mechanism leads to cancer metastasis and thereby death. In this perspective, we explored the antimetastatic potential and mechanism of curcumin on the EMT process by establishing in vitro EMT model in lungs cancer (A549) cells induced by TGF-ß1. Our results showed that curcumin mitigates EMT by regulating the expression of crucial mesenchymal markers such as MMP2, vimentin and N-cadherin. Besides, the transcriptional analysis revealed that the curcumin treatment differentially regulated the expression of 75 genes in NanoString nCounter platform. Further protein-protein interaction network and clusters analysis of differentially expressed genes revealed their involvement in essential biological processes that plays a key role during EMT transition. Altogether, the study provides a comprehensive overview of the antimetastatic potential of curcumin in TGF-ß1-induced EMT in lung cancer cells. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03360-7.

Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids.

Cancer is a complex disease, and its treatment is a big challenge, with variable efficacy of conventional anticancer drugs. A two-drug cocktail hybrid approach is a potential strategy in recent drug discovery that involves the combination of two drug pharmacophores into a single molecule. The hybrid molecule acts through distinct modes of action on several targets at a given time with more efficacy and less susceptibility to resistance. Thus, there is a huge scope for using hybrid compounds to tackle the present difficulties in cancer medicine. Recent work has applied this technique to uncover some interesting molecules with substantial anticancer properties. In this study, we report data on numerous promising hybrid anti-proliferative/anti-tumor agents developed over the previous 10 years (2011-2021). It includes quinazoline, indole, carbazole, pyrimidine, quinoline, quinone, imidazole, selenium, platinum, hydroxamic acid, ferrocene, curcumin, triazole, benzimidazole, isatin, pyrrolo benzodiazepine (PBD), chalcone, coumarin, nitrogen mustard, pyrazole, and pyridine-based anticancer hybrids produced via molecular hybridization techniques. Overall, this review offers a clear indication of the potential benefits of merging pharmacophoric subunits from multiple different known chemical prototypes to produce more potent and precise hybrid compounds. This provides valuable knowledge for researchers working on complex diseases such as cancer.

Cucumis melo var. momordica as a Potent Antidiabetic, Antioxidant and Possible Anticovid Alternative: Investigation through Experimental and Computational Methods.

Diabetes mellitus is a typical life threatening of disease, which generate due to the dysfunction of ß cells of pancreas. In 2014, WHO stated that 422 million people were infected with DM. The current pattern of management of diabetes included synthetic or plant based oral hypoglycemic drugs and insulin but drug resentence is become a very big issues in antidiabetic therapy. Thus, it's very earnest to discover now medication for this disease. Now the days, it is well acknowledged that diabetic patients are more prone towards covid and related complications. Thus, medical practitioners reformed the methodology of prescribing medication for covid infected antidiabetic therapy and encouraging the medication contains dual pharmacological properties. It is also well know that polyphenols specifically hold a significant role in oxidative stress and reduced the severity of many inflammatory diseases. Cucumis melo has rich history as ethano-pharmacological use in Indian subcontinent. The fruit and seed are well-known for the treatment of various diseases due to the presence of phenolics. Therefore, in this study, the combined mixture of flower and seeds were used for the extraction of polyphenolic rich extract and tested for antidiabetic activity through the antioxidant and in vivo experiments. The antioxidant potential measurement exhibited that the selected plant extract has the significant competence to down-regulate oxidative stress (DPPH scavenging IC50 at 60.7±1.05 µg/mL, ABTS IC50 at 62.15±0.50 µg/mL). Furthermore, the major polyphenolic phyto-compounds derived from the Cucumis melo were used for in silico anticovid activity, docking, and complementarity studies. The anticovid activity prognosis reflected that selected phyto-compounds amentoflavone and vanillic acid have optimal possibility to interact with 3C-like protease and through this moderate anticovid activity can be exhibit. The docking experiments established that the selected compounds have propensity to interact with protein tyrosine phosphatase 1B, 11ß-Hydroxysteroid dehydrogenase, superoxide dismutase, glutathione peroxidase, and catalase ß-glucuronidase receptor. In vivo experiments showed that 500 mg/kg, Cucumis melo extract ominously amplified body weight, plasma insulin, high-density lipoprotein levels, and biochemical markers. Furthermore, extract significantly downregulate the blood glucose, total cholesterol, triglycerides, low-density lipoprotein, and very low-density lipoprotein.

Debelalactone Prevents Hepatic Cancer via Diminishing the Inflammatory Response and Oxidative Stress on Male Wistar Rats.

The current study was conducted to exemplify the effect of debelalactone on tissue protection, chronic hepatic inflammation, hepatic protection and oxidative stress induced by diethyl nitrosamine in Wistar rats. Therefore, DEN (200 mg/kg) was used for the induction the hepatocellular carcinoma (HCC) and the level of serum alpha fetoprotein was used for the estimation and confirmation of HCC. The study illustrated that debelalactone (DL) significantly downregulated the hepatic, non-hepatic parameters such as aspartate aminotransferase, alanine aminotransferase, alpha fetoprotein, NO levels, total protein, albumin, blood urea nitrogen, total bilirubin, and direct bilirubin in dose dependent manner, as well as noticeably improving the body weight, of treated animals. The macroscopically observation of DEN-induced rat liver showed the formation of informalities in liver tissue, which was reduced with treatment of DL at dose dependent manner. However, antioxidant markers and inflammatory mediators such as lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase and transferase, TNF-α, IL-1ß, IL-6, and NF-kB restored up to the normal level by DL. The histopathology studies showed that the treated group of animals returned to a normal status. Collectively, it can be concluded that debelalactone mediated chemoprevention in the DEN-induced rats via an increase in the activities of endogenous enzymes and/or inhibition the precancerous cells.

Withasomniferol C, a new potential SARS-CoV-2 main protease inhibitor from the Withania somnifera plant proposed by in silico approaches.

Exploring potent herbal medicine candidates is a promising strategy for combating a pandemic in the present global health crisis. In Ayurveda (a traditional medicine system in India), Withania somnifera (WS) is one of the most important herbs and it has been used for millennia as Rasayana (a type of juice) for its wide-ranging health benefits. WS phytocompounds display a broad spectrum of biological activities (such as antioxidant, anticancer and antimicrobial) modulate detoxifying enzymes, and enhance immunity. Inspired by the numerous biological actions of WS phytocompounds, the present investigation explored the potential of the WS phytocompounds against the SARS-CoV-2 main protease (3CLpro). We selected 11 specific withanolide compounds, such as withaphysalin, withasomniferol, and withafastuosin, through manual literature curation against 3CLpro. A molecular similarity analysis showed their similarity with compounds that have an established inhibitory activity against the SARS-CoV-2. In silico molecular docking and molecular dynamics simulations elucidated withasomniferol C (WS11) as a potential candidate against SARS-CoV-2 3CLpro. Additionally, the present work also presents a new method of validating docking poses using the AlteQ method.

Proposition of a new allosteric binding site for potential SARS-CoV-2 3CL protease inhibitors by utilizing molecular dynamics simulations and ensemble docking.

The SARS-CoV-2 3CL protease (3CLpro) shows a high similarity with 3CL proteases of other beta-coronaviruses, such as SARS and MERS. It is the main enzyme involved in generating various non-structural proteins that are important for viral replication and is one of the most important proteins responsible for SARS-CoV-2 virulence. In this study, we have conducted an ensemble docking of molecules from the DrugBank database using both the crystallographic structure of the SARS-CoV-2 3CLpro, as well as five conformations obtained after performing a cluster analysis of a 300 ns molecular dynamics (MD) simulation. This procedure elucidated the inappropriateness of the active site for non-covalent inhibitors, but it has also shown that there exists an additional, more favorable, allosteric binding site, which could be a better target for non-covalent inhibitors, as it could prevent dimerization and activation of SARS-CoV-2 3CLpro. Two such examples are radotinib and nilotinib, tyrosine kinase inhibitors already in use for treatment of leukemia and which binding to the newly found allosteric binding site was also confirmed using MD simulations. Communicated by Ramaswamy H. Sarma.

The study of EGFR-ligand complex electron property relationship with biological activity.

The present investigation grounded on estimation of electron properties of the structures of EGFR proteins-ligand complexes using our laboratory-developed methodology AlteQ approach, which describes the molecular electron density of the complex in space for a certain point in three-dimensional coordinates. Briefly, the system embodies molecular electron density as a sum of Slater's type atomic increments of the molecular system. Further, using this methodology, we calculated different electron characteristics of selected EGFR protein-ligand complexes and established the relationship between different electron properties with their experimental pharmacological activity value (pIC50). The study suggested that EGFR inhibitory activity has higher correlation with intermolecular contacts of H with pi-system of aromatic ring between protein and ligands. Therefore, this created model has impact to identify and design potential ligands against EGFR in anticancer drug discovery.Communicated by Ramaswamy H. Sarma.