The Interplay of Spacer Chirality and Parity in Mesogenic Dimers.

Introducing chirality into soft materials, including liquid crystals (LCs), profoundly impacts their self-organization and physical properties. In this study, we synthesized a novel series of LC dimers with a chiral center as part of their flexible spacer. The dimers were prepared in racemic and enantiomerically pure forms. Their spacer length and parity were varied to investigate the effect of spacer chirality and parity on mesomorphic behavior and on chiral induction in the nematic phase of achiral mesogens. Our results show that the even-membered chiral dimers only have chiral nematic phases. In contrast, the odd-membered dimers display rich mesomorphism, including the intriguing blue phase (BP) and chiral form of the twist-bend nematic phase (N*TB). The observed significant difference in the 3D surface morphology between the racemic and chiral forms of the N*TB phase suggests that the chiral moiety in the spacer promotes a chiral hierarchy. Furthermore, the chiral dimers show a prominent odd-even effect in the helical twisting power in nematic hosts. These findings highlight the importance of the position of the chiral group within the dimeric molecule and provide new insights into how intrinsic chirality in the spacer affects the overall structural chirality.

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.

Platinum(IV) compounds as potential drugs: a quantitative structure-activity relationship study.

Introduction: Machine learning methods, coupled with a tremendous increase in computer power in recent years, are promising tools in modern drug design and drug repurposing. Methods: Machine learning predictive models, publicly available at chemosophia.com, were used to predict the bioactivity of recently synthesized platinum(IV) complexes against different kinds of diseases and medical conditions. Two novel QSAR models based on the BiS algorithm are developed and validated, capable to predict activities against the SARS-CoV virus and its RNA dependent RNA polymerase. Results: The internal predictive power of the QSAR models was tested by 10-fold cross-validation, giving cross-R2 from 0.863 to 0.903. 38 different activities, ranging from antioxidant, antibacterial, and antiviral activities, to potential anti-inflammatory, anti-arrhythmic and anti-malarial activity were predicted for a series of eighteen platinum(IV) complexes. Conclusion: Complexes 1, 3 and 13 have high generalized optimality criteria and are predicted as potential SARS-CoV RNA dependent RNA polymerase inhibitors.

Limited Cheese Intake Paradigm Replaces Patterns of Behavioral Disorders in Experimental PTSD: Focus on Resveratrol Supplementation.

Currently, the efficacy of drug therapy for post-traumatic stress disorder or PTSD leaves much to be desired, making nutraceutical support a promising avenue for treatment. Recent research has identified the protective effects of resveratrol in PTSD. Here, we tested the behavioral and neurobiological effects of combining cheese consumption with resveratrol supplements in an experimental PTSD model. Using the elevated plus maze test, we observed that cheese intake resulted in a shift from anxiety-like behavior to depressive behavior, evident in increased freezing acts. However, no significant changes in the anxiety index value were observed. Interestingly, supplementation with cheese and resveratrol only led to the elimination of freezing behavior in half of the PTSD rats. We further segregated the rats into two groups based on freezing behavior: Freezing+ and Freezing0 phenotypes. Resveratrol ameliorated the abnormalities in Monoamine Oxidize -A and Brain-Derived Neurotrophic Factor gene expression in the hippocampus, but only in the Freezing0 rats. Moreover, a negative correlation was found between the number of freezing acts and the levels of Monoamine Oxidize-A and Brain-Derived Neurotrophic Factor mRNAs in the hippocampus. The study results show promise for resveratrol supplementation in PTSD treatment. Further research is warranted to better understand the underlying mechanisms and optimize the potential benefits of resveratrol supplementation for PTSD.

Structural Modifications Introduced by NS2B Cofactor Binding to the NS3 Protease of the Kyasanur Forest Disease Virus.

Kyasanur Forest Disease virus (KFDV), a neglected human pathogenic virus, is a Flavivirus that causes severe hemorrhagic fever in humans. KFDV is transmitted to humans by the bite of the hard tick (Haemaphysalis spinigera), which acts as a reservoir of KFDV. The recent expansion of the endemic area of KFDV is of concern and requires the development of new preventive measures against KFDV. Currently, there is no antiviral therapy against KFDV, and the existing vaccine has limited efficacy. To develop a new antiviral therapy against KFDV, we focused on the nonstructural proteins NS2B and NS3 of KFDV, which are responsible for serine protease activity. Viral proteases have shown to be suitable therapeutic targets in the development of antiviral drugs against many diseases. However, success has been limited in flaviviruses, mainly because of the important features of the active site, which is flat and highly charged. In this context, the present study focuses on the dynamics of NS2B and NS3 to identify potential allosteric sites in the NS2B/NS3 protease of KDFV. To our knowledge, there are no reports on the dynamics of NS2B and NS3 in KFDV, and the crystal structure of the NS2B/NS3 protease of KFDV has not yet been solved. Overall, we created the structure of the NS2B/NS3 protease of KFDV using AlphaFold and performed molecular dynamics simulations with and without NS2B cofactor to investigate structural rearrangements due to cofactor binding and to identify alternative allosteric sites. The identified allosteric site is promising due to its geometric and physicochemical properties and druggability and can be used for new drug development. The applicability of the proposed allosteric binding sites was verified for the best-hit molecules from the virtual screening and MD simulations.

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.

Resistance to Resveratrol Treatment in Experimental PTSD Is Associated with Abnormalities in Hepatic Metabolism of Glucocorticoids.

Glucocorticoids are metabolized by the CYP3A isoform of cytochrome P450 and by 11-ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1). Experimental data suggest that post-traumatic stress disorder (PTSD) is associated with an increase in hepatic 11ß-HSD-1 activity and a concomitant decrease in hepatic CYP3A activity. Trans-resveratrol, a natural polyphenol, has been extensively studied for its antipsychiatric properties. Recently, protective effects of trans-resveratrol were found in relation to PTSD. Treatment of PTSD rats with trans-resveratrol allowed the rats to be divided into two phenotypes. The first phenotype is treatment-sensitive rats (TSR), and the second phenotype is treatment-resistant rats (TRRs). In TSR rats, trans-resveratrol ameliorated anxiety-like behavior and reversed plasma corticosterone concentration abnormalities. In contrast, in TRR rats, trans-resveratrol aggravated anxiety-like behavior and decreased plasma corticosterone concentration. In TSR rats, hepatic 11ß-HSD-1 activity was suppressed, with a concomitant increase in CYP3A activity. In TRR rats, the activities of both enzymes were suppressed. Thus, the resistance of PTSD rats to trans-resveratrol treatment is associated with abnormalities in hepatic metabolism of glucocorticoids. The free energy of binding of resveratrol, cortisol, and corticosterone to the human CYP3A protein was determined using the molecular mechanics Poisson-Boltzmann surface area approach, indicating that resveratrol could affect CYP3A activity.

Can Resveratrol Influence the Activity of 11ß-Hydroxysteroid Dehydrogenase Type 1? A Combined In Silico and In Vivo Study.

The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) is an NADPH-dependent reductase, responsible for the activation of cortisol by reducing cortisone. Resveratrol (RES), a type of natural polyphenol, is reported to be able to slow the progression of cancer and cardiovascular disease and improve the health of mice on a high-calorie diet. In this article, we applied molecular docking and molecular dynamics simulations to investigate the possibility of binding RES to 11ß-HSD-1. The 11ß-HSD-1:RES complex is stable on the µs time scale, and backbone RMSD-based clustering identified three conformations. Special attention was paid to the interaction pattern between the ligand and the target molecule, revealing hydrogen bonds between the hydroxyl group of RES and Thr124, as well as hydrophobic interactions responsible for the binding. In vivo studies demonstrated the ability of resveratrol at a dose of 40 mg/kg to reduce 11ß-HSD-1 activity in the liver of rats under conditions of experimental post-traumatic stress disorder (PTSD), as well as in non-stressed animals. In both cases, the resveratrol-induced reduction in 11ß-HSD-1 activity was accompanied by an increase in plasma corticosterone levels and a decrease in anxiety levels in the plus maze test.

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.

AlteQ: a new complementarity principle-centered method for the evaluation of docking poses.

Molecular docking is the most popular and widely used method for identifying novel molecules against a target of interest. However, docking procedures and their validation are still under intense development. In the present investigation, we evaluate a quantum free-orbital AlteQ method for evaluating docking complexes generated by taking EGFR complexes as an example. The AlteQ method calculates the electron density using Slater's type atomic contributions in the interspace between the receptor and the ligand. Since the interactions are determined by the overlap of electron clouds, they follow the complementarity principle, and an equation can be obtained that describes these interactions. The AlteQ method evaluates the quality of the interaction between the receptor and the ligand, how complementary the interactions are, and due to this, it is used to reject less realistic structures obtained by docking methods. Here, three different equations were used to determine the quality of the interactions in experimental complexes and docked complexes obtained using AutoDock Vina and AutoDock 4.2.6.Communicated by Ramaswamy H. Sarma.

The design of compounds with desirable properties - The anti-HIV case study.

Efficacy and safety are among the most desirable characteristics of an ideal drug. The tremendous increase in computing power and the entry of artificial intelligence into the field of computational drug design are accelerating the process of identifying, developing, and optimizing potential drugs. Here, we present novel approach to design new molecules with desired properties. We combined various neural networks and linear regression algorithms to build models for cytotoxicity and anti-HIV activity based on Continual Molecular Interior analysis (CoMIn) and Cinderella's Shoe (CiS) derived molecular descriptors. After validating the reliability of the models, a genetic algorithm was coupled with the Des-Pot Grid algorithm to generate new molecules from a predefined pool of molecular fragments and predict their bioactivity and cytotoxicity. This combination led to the proposal of 16 hit molecules with high anti-HIV activity and low cytotoxicity. The anti-SARS-CoV-2 activity of the hits was predicted.

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.

On the propensity of formation of cyclobutane dimers in face-to-face and face-to-back uracil stacks in solution.

UV irradiation of RNA leads to the formation of intra- and inter-strand crosslinks of cyclobutane type. Despite the importance of this reaction, relatively little is known about how the mutual orientation of the two bases affects the outcome of the reaction. Here we report a comparative nonadiabatic molecular dynamics study of face-to-back (F2B) and face-to-face (F2F) stacked uracil-water clusters. The computations were performed using the second-order algebraic-diagrammatic-construction (ADC(2)) method. We found that F2B stacked uracil-water clusters either relax non-reactively to the ground state by an ethylenic twist around the CC bond or remain in the lowest nπ* state in which the two bases gradually move away from each other. This finding is consistent with the low propensity for the formation of intra-strand cyclobutane dimers between adjacent RNA bases. On the contrary, in F2F stacked uracil-water clusters, in addition to non-reactive deactivation, we found a pro-reactive deactivation pathway, which may lead to the formation of cyclobutane uracil dimers in the electronic ground state. On a qualitative level, the observed photodynamics of F2F stacked uracil-water clusters explains the greater propensity of RNA to form inter-strand cyclobutane-type crosslinks.

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.

A new glimpse on the active site of SARS-CoV-2 3CLpro, coupled with drug repurposing study.

Coronavirus disease 2019 (COVID-19) is caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). Its main protease, 3C-like protease (3CLpro), is an attractive target for drug design, due to its importance in virus replication. The analysis of the radial distribution function of 159 3CLpro structures reveals a high similarity index. A study of the catalytic pocket of 3CLpro with bound inhibitors reveals that the influence of the inhibitors is local, perturbing dominantly only residues in the active pocket. A machine learning based model with high predictive ability against SARS-CoV-2 3CLpro is designed and validated. The model is used to perform a drug-repurposing study, with the main aim to identify existing drugs with the highest 3CLpro inhibition power. Among antiviral agents, lopinavir, idoxuridine, paritaprevir, and favipiravir showed the highest inhibition potential. Enzyme - ligand interactions as a key ingredient for successful drug design.

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.

Electronic properties investigation of human dihydrofolate reductase complexes with ligands.

Despite the fact that there are already drugs for cancer, they still show strong toxicity to the human organism. That is why it is necessary to establish the factors affecting activity in order to develop new, more effective drugs aimed at tumor cells, minimizing harm to healthy cells. The present research is based on electronic properties calculation of the complexes using AlteQ approach. In the focus of this study are complexes of human dihydrofolate reductase (hDHFR) with a series of known inhibitors bound in the active site. Further, a statistical analysis was performed to establish the relationships between a myriad electronic characteristics and IC50. The change in total volume and the change of own electrons number of hydrogen atoms in their atomic basins are identified as the descriptors correlating the most with the hDHFR inhibition potency. Additionally, two lipophilic parts of protein (Thr56, Ser59, Ile60 and Ile7, Val8, Ala9) were found, which act as a key factor in decreasing bioactivity. The depth analysis of intermolecular interactions showed that the interactions between water molecules and ligand play a crucial role in hDHFR inhibition. Furthermore, the molecular dynamics simulations were used for deeper understanding of the structural inhibition, each for 50 ns time scale in explicit water conditions. Thus, the AlteQ approach made it possible to determine the factors influencing the activity and evaluate them not only qualitatively, but also quantitatively.Communicated by Ramaswamy H. Sarma.

Exploring potential inhibitors against Kyasanur forest disease by utilizing molecular dynamics simulations and ensemble docking.

Kyasanur forest disease (KFD) is a tick-borne, neglected tropical disease, caused by KFD virus (KFDV) which belongs to Flavivirus (Flaviviridae family). This emerging viral disease is a major threat to humans. Currently, vaccination is the only controlling method against the KFDV, and its effectiveness is very low. An effective control strategy is required to combat this emerging tropical disease using the existing resources. In this regard, in silico drug repurposing method offers an effective strategy to find suitable antiviral drugs against KFDV proteins. Drug repurposing is an effective strategy to identify new use for approved or investigational drugs that are outside the scope of their initial usage and the repurposed drugs have lower risk and higher safety compared to de novo developed drugs, because their toxicity and safety issues are profoundly investigated during the preclinical trials in human/other models. In the present work, we evaluated the effectiveness of the FDA approved and natural compounds against KFDV proteins using in silico molecular docking and molecular simulations. At present, no experimentally solved 3D structures for the KFD viral proteins are available in Protein Data Bank and hence their homology model was developed and used for the analysis. The present analysis successfully developed the reliable homology model of NS3 of KFDV, in terms of geometry and energy contour. Further, in silico molecular docking and molecular dynamics simulations successfully presented four FDA approved drugs and one natural compound against the NS3 homology model of KFDV. Communicated by Ramaswamy H. Sarma.

Anti-neoplastic pharmacophore benzophenone-1 coumarin (BP-1C) targets JAK2 to induce apoptosis in lung cancer.

Reigning of the abnormal gene activation associated with survival signalling in lung cancer leads to the anomalous growth and therapeutic failure. Targeting specific cell survival signalling like JAK2/STAT3 nexus has become a major focus of investigation to establish a target specific treatment. The 2-bromobenzoyl-4-methylphenoxy-acetyl hydra acetyl Coumarin (BP-1C), is new anti-neoplastic agent with apoptosis inducing capacity. The current study was aimed to develop antitumor phramacophore, BP-1C as JAK2 specific inhibitor against lung neoplastic progression. The study validates and identifies the molecular targets of BP-1C induced cell death. Cell based screening against multiple cancer cell lines identified, lung adenocarcinoma as its specific target through promotion of apoptosis. The BP-1C is able to induce, specific hall marks of apoptosis and there by conferring anti-neoplastic activity. Validation of its molecular mechanism, identified, BP-1C specifically targets JAK2Tyr1007/1008 phosphorylation, and inhibits its downstream STAT3Tyr705 signalling pathway to induce cell death. As a consequence, modulation in Akt/Src survival signal and altered expression of interwoven apoptotic genes were evident. The results were reproducible in an in-vivo LLC tumor model and in-ovo xenograft studies. The computational approaches viz, drug finger printing confers, BP-1C as novel class JAK2 inhibitor and molecular simulations studies assures its efficiency in binding with JAK2. Overall, BP-1C is a novel JAK2 inhibitor with experimental evidence and could be effectively developed into a promising drug for lung cancer treatment.