Hybrid Virtual Screening Approach to Predict Novel Natural Compounds against HIV-1 CCR5.

BACKGROUND: Human immunodeficiency virus (HIV) infection continues to pose a major global health challenge. HIV entry into host cells via membrane fusion mediated by the viral envelope glycoprotein gp120/gp41 is a key step in the HIV life cycle. CCR5, expressed on CD4+ T cells and macrophages, acts as a coreceptor facilitating HIV-1 entry. The CCR5 antagonist maraviroc is used to treat HIV infection. However, it can cause adverse effects and has limitations such as only inhibiting CCR5-tropic viruses. There remains a need to develop alternative CCR5 inhibitors with improved safety profiles. PROBLEM STATEMENT: Natural products may offer advantages over synthetic inhibitors including higher bioavailability, binding affinity, effectiveness, lower toxicity, and molecular diversity. However, screening the vast chemical space of natural compounds to identify novel CCR5 inhibitors presents challenges. This study aimed to address this gap through a hybrid ligand-based pharmacophore modeling and molecular docking approach to virtually screen large natural product databases. METHODS: A reliable pharmacophore model was developed based on 311 known CCR5 antagonists and validated against an external data set. Five natural product databases containing over 306,000 compounds were filtered based on drug-likeness rules. The validated pharmacophore model screened the databases to identify 611 hits. Key residues of the CCR5 receptor crystal structure were identified for docking. The top hits were docked, and interactions were analyzed. Molecular dynamics simulations were conducted to examine complex stability. Computational prediction evaluated pharmacokinetic properties. RESULTS: Three compounds exhibited similar interactions and binding energies to maraviroc. MD simulations demonstrated complex stability comparable to maraviroc. One compound showed optimal predicted absorption, minimal metabolism, and a lower likelihood of interactions than maraviroc. CONCLUSION: This computational screening workflow identified three natural compounds with promising CCR5 inhibition and favorable pharmacokinetic profiles. One compound emerged as a lead based on bioavailability potential and minimal interaction risk. These findings present opportunities for developing alternative CCR5 antagonists and warrant further experimental investigation. Overall, the hybrid virtual screening approach proved effective for mining large natural product spaces to discover novel molecular entities with drug-like properties.

Tepotinib and tivantinib as potential inhibitors for the serine/threonine kinase of the mpox virus: insights from structural bioinformatics analysis.

The serine/threonine kinase (STK) plays a central role as the primary kinase in poxviruses, directing phosphoryl transfer reactions. Such reactions are pivotal for the activation of certain proteins during viral replication, assembly, and maturation. Therefore, targeting this key protein is anticipated to impede virus replication. In this work, a structural bioinformatics approach was employed to evaluate the potential of drug-like kinase inhibitors in binding to the ATP-binding pocket on the STK of the Mpox virus. Virtual screening of known kinase inhibitors revealed that the top 10 inhibitors exhibited binding affinities ranging from -8.59 to -12.05 kcal/mol. The rescoring of compounds using the deep-learning default model in GNINA was performed to predict accurate binding poses. Subsequently, the top three inhibitors underwent unbiased molecular dynamics (MD) simulations for 100 ns. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and Principal Component Analysis (PCA) suggested tepotinib as a competitive inhibitor for Mpox virus STK as evidenced by its binding free energy and the induction of similar conformational behavior of the enzyme. Nevertheless, it is sensible to experimentally test all top 10 compounds, as scoring functions and energy calculations may not consistently align with experimental findings. These insights are poised to provide an attempt to identify an effective inhibitor for the Mpox virus.Communicated by Ramaswamy H. Sarma.

Prediction of the binding location between the nuclear inhibitor of DNA binding and differentiation 2 (ID2) and HSPA5.

Glucose-regulated protein 78 (GRP78), also termed HSPA5, was widely studied in cancer. It was recently approved that GRP78 has nuclear localization potential that sheds light on its role in cancer development. The inhibitor of DNA binding and differentiation 2 (ID2) is the nuclear component that associates with GRP78. The interaction between these two proteins is not understood clearly. In the current study, the binding pattern of GRP78/ID2 is predicted using computational methods. Protein-protein docking is used along with molecular dynamics simulation. The substrate binding domain ß of GRP78 can stably interact with the loop region (C42-S60) of ID2 as predicted in this study. This paves the way for a possible destabilizer for this association and cancer eradication.

Binding site prediction between lysozyme and glucose-regulated protein 78, a hope to fight amyloidosis.

Amyloidosis is an extraordinarily vigorous and heterogeneous group of disorders that causes numerous organ failures due to the precipitation of misfolded proteins. Many of these damaged proteins are discarded before causing any fatal diseases due to the contribution of the protein quality control (PQC) system and its chaperons, including glucose-regulated protein (GRP78). One of the most important enzymatic proteins inside the body is lysozyme, which is reported to have many mutated variants that may cause amyloid fibrils. This study used structural bioinformatics and molecular dynamics simulations to test and suggest binding sites for the human lysozyme protein with GRP78. Multiple sequence alignment (MSA) shows that part of the lysozyme envelope protein (C65-C81 cyclic region) has high similarities (30.77% identity) with the cyclic Pep42. Additionally, the binding between the lysozyme cyclic region (C65-C81) and GRP78 substrate binding domain (SBD) is found favorable. The number and types of interactions vary between each of the mutant isoforms of lysozyme. The more significant the conformational changes in the mutation, the greater its probability of aggregation and the formation of amyloid fibrils. Each mutation leads to different interactions and binding patterns with GRP78. The present computational study suggests a lysozyme-GRP78 binding site, thus paving the way for drug designers to construct suitable carriers that can collect misfolded lysozyme proteins and eliminate them from the body, preventing their aggregation and amyloidogenesis.Communicated by Ramaswamy H. Sarma.

Triple in silico targeting of IMPDH enzyme and RNA-dependent RNA polymerase of both SARS-CoV-2 and Rhizopus oryzae.

Aim: Mucormycosis has been associated with SARS-CoV-2 infections during the last year. The aim of this study was to triple-hit viral and fungal RNA-dependent RNA polymerases (RdRps) and human inosine monophosphate dehydrogenase (IMPDH). Materials & methods: Molecular docking and molecular dynamics simulation were used to test nucleotide inhibitors (NIs) against the RdRps of SARS-CoV-2 and Rhizopus oryzae RdRp. These same inhibitors targeted IMPDH. Results: Four NIs revealed a comparable binding affinity to the two drugs, remdesivir and sofosbuvir. Binding energies were calculated using the most abundant conformations of the RdRps after 100-ns molecular dynamics simulation. Conclusion: We suggest the triple-inhibition potential of four NIs against pathogenic RdRps and IMPDH, which is worth experimental validation.

In silico targeting of SARS-CoV-2 spike receptor-binding domain from different variants with chaga mushroom terpenoids.

Terpenoids from the chaga mushroom have been identified as potential antiviral agents against SARS-CoV-2. This is because it can firmly bind to the viral spike receptor binding domain (RBD) and the auxiliary host cell receptor glucose-regulated protein 78 (GRP78). The current work examines the association of the chaga mushroom terpenoids with the RBD of various SARS-CoV-2 variants, including alpha, beta, gamma, delta, and omicron. This association was compared to the SARS-CoV-2 wild-type (WT) RBD using molecular docking analysis and molecular dynamics modeling. The outcomes demonstrated that the mutant RBDs, which had marginally greater average binding affinities (better binding) than the WT, were successfully inhibited by the chaga mushroom terpenoids. The results suggest that the chaga mushroom can be effective against various SARS-CoV-2 variants by targeting both the host-cell surface receptor GRP78 and the viral spike RBD.Communicated by Ramaswamy H. Sarma.

In vivo dose measurements for tangential field-in-field ultra-hypofractionated breast radiotherapy.

INTRODUCTION: Ultra-hypofractionated radiotherapy (UHF-RT) mandates more accuracy in each part of the treatment cycle to maximize cure rates and minimize toxicities. In vivo dosimetry is a direct method for verifying overall treatment accuracy. This study evaluated uncertainties in the delivered dose of Hypofractionated (HF) and UHF Whole Breast Irradiation (WBI) and to analyze the accuracy of the workflow to pave the way for a wide-scale use of UHF-RT. METHODS: Thirty-three breast cancer cases, including 16 HF-WBI and 17 UHF-WBI were treated with 3D conformal Radiotherapy (3D-CRT), where 79 fields were analyzed for dose verification. The measurement point was set at the beam entrance (1.5 cm depth). The expected dose at Dmax was calculated via TPS. Before in vivo measurements, diode detectors were tested and calibrated. We developed initial validation measurements for UHF-RT on an anthropomorphic breast phantom for the first time. RESULTS: For RANDO phantom, the percentage difference between measured and calculated doses showed an average of -0.52 ± 5.4%, in addition to an excellent dose reproducibility within 0.6%. The overall in vivo measurements for studied cases showed that 83.5% of the measured doses were within ±5% and only 1.8% of the measured doses were greater than ±10% of the calculated doses. The percentage accuracy was slightly larger for UHF cohort (84.2%) compared to HF cohort (83.2%). The maximum percentage difference between them was less than 1%. CONCLUSION: Breast in vivo dosimetry is an adequate tool for treatment verification that improves the accuracy of the treatment cycle. UHF-RT may contribute in reducing the long waiting lists, increasing patient convenience, and saving the available resources for breast cancer patients.

Molecular dynamics simulations and MM-GBSA reveal a novel small molecule against Flu A RNA-dependent RNA polymerase.

The interaction between the C-terminal domain (CTD) of the polymerase acidic (PA) component of three Flu A RNA polymerases of different origins and three heptad repeats from human polymerase II CTD was computationally recreated. Then a unique pharmacological library was tested in order to target conserved active site residues in the three RNA-dependent RNA polymerase (RdRps) using a combination of molecular dynamics simulation and molecular docking. Results show that one compound (ZINC66032798) can effectively bind to the desired active site residues in each of the three RdRps. Hence, it may possess an inhibitory action by competing with human polymerase II CTD binding to the same active site of the viruses. The current in silico analysis suggests a promising novel lead to block Flu A RdRp, yet to be confirmed in the wet lab. It decreases the binding affinity of influenza A viruses to human polymerase II by 47.9%, 67.2%, and 28.0%, respectively.Communicated by Ramaswamy H. Sarma.

Novel sofosbuvir derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective.

The human coronavirus, SARS-CoV-2, had a negative impact on both the economy and human health, and the emerging resistant variants are an ongoing threat. One essential protein to target to prevent virus replication is the viral RNA-dependent RNA polymerase (RdRp). Sofosbuvir, a uridine nucleotide analog that potently inhibits viral polymerase, has been found to help treat SARS-CoV-2 patients. This work combines molecular docking and dynamics simulation (MDS) to test 14 sofosbuvir-based modifications against SARS-CoV-2 RdRp. The results reveal comparable (slightly better) average binding affinity of five modifications (compounds 3, 4, 11, 12, and 14) to the parent molecule, sofosbuvir. Compounds 3 and 4 show the best average binding affinities against SARS-CoV-2 RdRp (- 16.28 ± 5.69 and - 16.25 ± 5.78 kcal/mol average binding energy compared to - 16.20 ± 6.35 kcal/mol for sofosbuvir) calculated by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) after MDS. The present study proposes compounds 3 and 4 as potential SARS-CoV-2 RdRp blockers, although this has yet to be proven experimentally.

Chia seeds and coenzyme Q10 alleviate iron overload induced hepatorenal toxicity in mice via iron chelation and oxidative stress modulation.

Iron overload (IOL) can cause hepatorenal damage due to iron-mediated oxidative and mitochondrial damage. Remarkably, combining a natural iron chelator with an antioxidant can exert greater efficacy than monotherapy. Thus, the present study aimed to evaluate the efficacy of Chia and CoQ10 to chelate excess iron and prevent hepatorenal oxidative damage in IOL mice. Male Swiss albino mice (n = 49) were randomly assigned to seven groups: control, dietary Chia, CoQ10, IOL, IOL + Chia, IOL + CoQ10, and IOL + Chia + CoQ10. Computational chemistry indicates that the phytic acid found in the Chia seeds is stable, reactive, and able to bind to up to three iron ions (both Fe2+ and Fe3+). IOL induced a significant (P < 0.05) increase in serum iron, ferritin, transferrin, TIBC, TSI, RBCs, Hb, MCV, MCH, WBCs, AST, ALT, creatinine, and MDA. IOL causes a significant (P < 0.05) decrease in UIBC, platelets, and antioxidant molecules (GSH, SOD, CAT, and GR). Also, IOL elicits mitochondrial membrane change depolarization, and DNA fragmentation and suppresses mitochondrial DNA copies. Furthermore, substantial changes in hepatic and renal tissue, including hepatocellular necrosis and apoptosis, glomerular degeneration, glomerular basement membrane thickening, and tubular degeneration, were observed in the IOL group. Dietary Chia and CoQ10 induced significant (P < 0.05) amelioration in all the mentioned parameters. They can mostly repair the abnormal architecture of hepatic and renal tissues induced by IOL, as signified by normal sinusoids, normal central veins, and neither glomerular damage nor degenerated tubules. In conclusion, the combined treatment with Chia + CoQ10 exerts more pronounced efficacy than monotherapy in hepatorenal protection via chelating excess iron and improved cellular antioxidant status and hepatorenal mitochondrial function in IOL mice.

Serine/threonine kinase of Mpox virus: computational modeling and structural analysis.

Kinases catalyze phosphoryl transfer from a nucleoside triphosphate (usually ATP) to an amino acid on a protein for activation purposes. Although kinases are well-appreciated drug targets in different viruses and cancers, these enzymes in poxviruses received limited attention from the research community. In poxvirus, the production of infectious particles in the infected cells depends on a serine/threonine protein kinase (STK) that activates proteins implicated in the assembly of new virions. This work aimed to elucidate the structure and dynamics of the major kinase STK from Mpox virus (Orthopoxvirus). A state-of-the-art computational approach was employed to decipher the structure and dynamics of the STK using AlphaFold2 and molecular dynamics (MD) simulations. Although the predicted structure showed an atypical kinase, the overall structural fold is conserved. Binding free energy calculations via Molecular Mechanics/Generalized Born and Surface Area (MM/GBSA) determined the hotspot residues contributing to binding of ATP. The structural analysis in this work provides insights into the structure and behavior of STK in Mpox virus and possibly its closest members of Poxviridae. These findings also set the basis for setting up a thorough experimental investigation to understand the enzymatic mechanism, peptide substrate binding, and the development of small-molecule inhibitors against this kinase.Communicated by Ramaswamy H. Sarma.

Targeting of HPV E6 at the binding sites to the host-cell E6AP, p53, and the endoplasmic reticulum-resident chaperone, GRP78.

Background: Human papillomavirus (HPV) represents an etiological factor for many cancer types, especially cervical cancer. Its oncoprotein E6 sheds drug designers who aim to stop its cellular protein associations, such as p53 and E6AP. Recently, it was discovered that the host-cell chaperone glucose-regulated protein 78 (GRP78) plays a crucial function in HPV infectivity by association with the viral E6 and E7 proteins. Therefore, we aimed to test small molecules inhibitor that could contradict the association between E6 and cellular factors E6AP, GRP78, and p53. Methods: In this study, molecular docking protocol was elaborated to test 115 small molecule compounds against the three binding sites of HPV E6 to the host-cell proteins; E6AP, p53, and GRP78. After that, molecular dynamics simulation and free energy calculations were performed on the best three complexes. Results: The results reveal the potency of 18 compounds against the HPV E6 at different binding sites, which give lower free energies than paclitaxel (positive control). The best two compounds, hypericin, and anabsinthin, could bind effectively and stably during the 100 ns MD simulation period to HPV E6. The calculated average free energies for hypericin and anabsinthin are -18.76 and -14.40 kcal/mol, respectively. They formed stable complexes with the three binding sites by forming hydrophobic contacts. The key residues that stabilize the two ligands in HPV E6 binding sites are V31, Y32, V62, and Y70 (E6AP), P13, C16, T22, I23 and A46 (p53), and M1, V31, L50, L67, and Q107 (GRP78). Conclusions: The best two compounds, hypericin, and anabsinthin, are potential candidates against HPV E6 at the host-cell factors binding sites, hence could block the oncoprotein activity of E6 in infected cells. Further experimental validation is yet to be performed and suggested as future work.Communicated by Ramaswamy H. Sarma.

A structural-based virtual screening and in vitro validation reveals novel effective inhibitors for SARS-CoV-2 helicase and endoribonuclease.

Researchers worldwide are looking for molecules that might disrupt the COVID-19 life cycle. Endoribonuclease, which is responsible for processing viral RNA to avoid detection by the host defense system, and helicase, which is responsible for unwinding the RNA helices for replication, are two key non-structural proteins. This study performs a hierarchical structure-based virtual screening approach for NSP15 and helicase to reach compounds with high binding probabilities. In this investigation, we incorporated a variety of filtering strategies for predicting compound interactions. First, we evaluated 756,275 chemicals from four databases using a deep learning method (NCI, Drug Bank, Maybridge, and COCONUT). Following that, two docking techniques (extra precision and induced fit) were utilized to evaluate the compounds' binding affinity, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy calculation. Remarkably, two compounds (90616 and CNP0111740) exhibited high binding affinity values of -66.03 and -12.34 kcal/mol for helicase and NSP15, respectively. The VERO-E6 cell line was employed to test their in vitro therapeutic impact. The CC50 for CNP0111740 and 90616 were determined to be 102.767 µg/ml and 379.526 µg/ml, while the IC50 values were 140.176 µg/ml and 5.147 µg/ml, respectively. As a result, the selectivity index for CNP0111740 and 90616 is 0.73 and 73.73, respectively. Finally, these compounds were found to be novel, effective inhibitors for the virus; however, further in vivo validation is needed.Communicated by Ramaswamy H. Sarma.

Simulation of gold nanoparticle movement through normal and cancer cell membranes.

Gold nanoparticles (Au-NPs) have been used for a long time to target cancer cells. Different modalities have been suggested to utilize Au-NPs in cancer patients. We construct both normal and cancer cell membranes to simulate the Au-NP entry to understand better how it can penetrate the cancer cell membrane. We use molecular dynamics simulation (MDS) on both normal and cancer cell membrane models for 150 ns. At the same time, we prepared the Au-NP of spherical shape (16 nm radius) capped with citrate using MDS for 100 ns. Finally, we added the Au-NP close to the membranes and moved it using 1000 kJ mol-1 nm-1 force constant during the 7.7 ns MDS run. We analyzed the membranes in the presence and absence of the Au-NP and compared normal and cancer membranes. The results show that normal cell membranes have higher stability than cancer membranes. Additionally, Au-NP forms pore in the membranes that facilitate water and ions entry during the movement inside the lipid bilayer region. These pores are responsible for the enhanced response of Au-NP-loaded chemotherapeutic agents in cancer treatment.

New progresses on cell surface protein HSPA5/BiP/GRP78 in cancers and COVID-19.

Heat-shock-protein family A (Hsp70) member 5 (HSPA5), aliases GRP78 or BiP, is a protein encoded with 654 amino acids by the HSPA5 gene located on human chromosome 9q33.3. When the endoplasmic reticulum (ER) was stressed, HSPA5 translocated to the cell surface, the mitochondria, and the nucleus complexed with other proteins to execute its functions. On the cell surface, HSPA5/BiP/GRP78 can play diverse functional roles in cell viability, proliferation, apoptosis, attachments, and innate and adaptive immunity regulations, which lead to various diseases, including cancers and coronavirus disease 2019 (COVID-19). COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which caused the pandemic since the first outbreak in late December 2019. HSPA5, highly expressed in the malignant tumors, likely plays a critical role in SARS-CoV-2 invasion/attack in cancer patients via tumor tissues. In the current study, we review the newest research progresses on cell surface protein HSPA5 expressions, functions, and mechanisms for cancers and SARS-CoV-2 invasion. The therapeutic and prognostic significances and prospects in cancers and COVID-19 disease by targeting HSPA5 are also discussed. Targeting HSPA5 expression by natural products may imply the significance in clinical for both anti-COVID-19 and anti-cancers in the future.

How helpful were molecular dynamics simulations in shaping our understanding of SARS-CoV-2 spike protein dynamics?

The SARS-CoV-2 spike protein (S) represents an important viral component that is required for successful viral infection in humans owing to its essential role in recognition of and entry to host cells. The spike is also an appealing target for drug designers who develop vaccines and antivirals. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. MD simulations found that the higher affinity of SARS-CoV-2-S to ACE2 is linked to its unique residues that add extra electrostatic and van der Waal interactions in comparison to the SARS-CoV S. This illustrates the spread potential of the pandemic SARS-CoV-2 relative to the epidemic SARS-CoV. Different mutations at the S-ACE2 interface, which is believed to increase the transmission of the new variants, affected the behavior and binding interactions in different simulations. The contributions of glycans to the opening of S were revealed via simulations. The immune evasion of S was linked to the spatial distribution of glycans. This help the virus to escape the immune system recognition. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. This will pave the way to us preparing for the next pandemic as the computational tools are tailored to help fight new challenges.

Exploration of natural compounds against the human mpox virus DNA-dependent RNA polymerase in silico.

BACKGROUND: Last year, the human monkeypox virus (hMPXV) emerged as an alarming threat to the community, with a detectable outbreak outside the African continent for the first time. According to The American Centers for Disease Control and Prevention (CDC), the virus is reported globally, with 86,746 confirmed cases (until April 08, 2023). DNA-dependent RNA polymerase (DdRp) is an essential protein for viral replication; hence it is a promising drug target for developing antiviral drugs against DNA viruses. Therefore, this study was conducted to search for natural compounds that could provide scaffolds for RNA polymerase inhibitors. METHODS: In this study, the DdRp structure of hMPXV was modeled and used to screen the natural compounds database (COCONUT). The virtual screening revealed 15 compounds able to tightly bind to the active site of the DdRp (binding energies less than -7.0 kcal/mol) compared to the physiological nucleotide, guanosine triphosphate (GTP). Molecular dynamics simulation was then performed on the top four hits and compared to GTP RESULTS: The results revealed the potential of four compounds (comp289, comp295, comp441, and comp449) in binding the hMPXV DdRp active site with a comparable binding affinity (-17.06 ± 2.96, -11.6 ± 5.34, -14.85 ± 2.66, and -10.79 ± 4.49 kcal/mol) with GTP (-21.03 ± 7.55 kcal/mol) CONCLUSION: These findings may also pave the way for developing new hMPXV inhibitors based on natural product scaffolds. These results need further experimental validation but promising as it was validated by unbiased all-atom MD simulations and binding free energy calculations.

The discovery of novel antivirals for the treatment of mpox: is drug repurposing the answer?

INTRODUCTION: Drugs that have demonstrated good activity against any member of the Orthopoxvirus genus are good candidates for repurposing studies against the mpox virus (MPXV). The conserved biology of poxviruses has proven beneficial from a clinical virology perspective. Evolutionarily conserved proteins tend to function in a highly similar way. Indeed, the smallpox vaccine was found to be 85% effective in protecting humans from mpox virus infection. Similarly, tecovirimat, the drug of choice for smallpox infections, was recently repurposed as a treatment option for mpox cases in Europe. AREA COVERED: This review article focuses on drug repurposing strategies to combat the newly emerged MPXV outbreak. The viral and host cell protein targets are challenged with a bunch of drugs and drug-like molecules in silico, in vitro, and in vivo. Some drugs show promising results and can be repurposed to eradicate MPXV infection. The authors also highlight potential limitations and provide their expert perspectives. EXPERT OPINION: Overall, it is clear that we cannot solely rely on the conventional drug discovery pipeline to find new treatments, despite advances in computational and experimental advances in the last few decades. Drug repurposing has successfully identified good candidate drugs against MPXV as it is one of the Orthopoxvirus genus family. Tecovirimat, brincidofovir, and cidofovir have shown promising results in preventing virus propagation. Consequently, drug repurposing represents an important strategy for the fast identification of new therapeutic options.

Computational identification of drug-like marine natural products as potential RNA polymerase inhibitors against Nipah virus.

Nipah virus (NiV) has been an alarming threat to human populations in southern Asia for more than a decade. It is one of the most deadly viruses in the Mononegavirales order. Despite its high mortality rate and virulence, no chemotherapeutic agent or vaccine is publicly available. Hence, this work was conducted to computationally screen marine natural products database for drug-like potential inhibitors for the viral RNA-dependent RNA polymerase (RdRp). The structural model was subjected to molecular dynamics (MD) simulation to obtain the native ensemble of the protein. The CMNPDB dataset of marine natural products was filtered to retain only compounds following Lipinski's five rules. The molecules were energy minimized and docked into different conformers of the RdRp using AutoDock Vina. The best 35 molecules were rescored by GNINA, a deep learning-based docking software. The resulting nine compounds were evaluated for their pharmacokinetic profiles and medicinal chemistry properties. The best five compounds were subjected to MD simulation for 100 ns, followed by binding free energy estimation via Molecular Mechanics/ Generalized Born Surface Area (MM/GBSA) calculations. The results showed remarkable behavior of five hits as inferred by stable binding pose and orientation to block the exit channel of RNA synthesis products in the RdRp cavity. These hits are promising starting materials for in vitro validation and structural modifications to enhance the pharmacokinetic and medicinal chemistry properties for developing antiviral lead compounds.

An insight into synthesis and antitumor activity of citrate and gallate stabilizing gold nanospheres.

Both gallic and citrate are well-established antioxidants that show promise as new selective anti-cancer drugs. Gold nanoparticles (AuNPs) as well can be developed as flexible and nontoxic nano-carriers for anti-cancer drugs. This article evaluating the efficiency and biocompatibility of gallic acid and citrate capping gold nanoparticles to be used as anti-cancer drug. The biosafety and therapeutic efficiency of prepared nano-formulations were tested on Hela and normal BHK cell line. Gold nanospheres coated with citrate and gallate were synthesized via wet chemical reduction method. The prepared nano-formulations, citrate and gallate coated gold nanospheres (Cit-AuNPs and Ga-AuNPs), were characterized with respect to their morphology, FTIR spectra, and physical properties. In addition, to assess their cytotoxicity, cell cycle arrest and flow cytometry to measure biological response were performed. Cit-Au NPs and Ga-Au NPs were shown to significantly reduce the viability of Hela cancer cells. Both G0/G cell cycle arrest and comet assay results showed that genotoxic effect was induced in Hela cells by Cit-Au NPs and Ga-Au NPs. The results of this study showed that Cit-Au NPs and Ga-AuNPs inhibit the growth of metastatic cervical cancer cells, which could have therapeutic implications.