Structure-based Screening Research Articles

A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis.

Neuronal ceroid-lipofuscinosis (NCLs) are a group of severe neurodegenerative conditions, most likely present in infantile, late infantile, juvenile, and adult-onset forms. Their phenotypic characteristics comprise eyesight damage, reduced motor activity and cognitive function, and sometimes tend to die in the initial stage. In recent studies, NCLs have been categorized into at least 14 genetic collections (CLN1-14). CLN2 gene encodes Tripeptidyl peptidase 1 (TPP1), which affects late infantile-onset form. In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD). Fifty-six missense mutants were enumerated with computational methods to perceive the significant mutants (G475R and G501C) and correlated with clinical and literature data. A structure-based screening method was initiated to understand protein-ligand interaction and dynamic simulation. The docking procedure was performed for the native (3EDY) and mutant (G473R and G501C) structures with Gemfibrozil (gem), which lowers the lipid level, decreases the triglycerides amount in the blood circulation, and controls hyperlipidemia. The Native had an interaction score of -5.57kcal/mol, and the mutants had respective average binding scores of -6.24 (G473R) and - 5.17 (G501C) kcal/mol. Finally, molecular dynamics simulation showed that G473R and G501C mutants had better flexible and stable orientation in all trajectory analyses. Therefore, this work gives an extended understanding of both functional and structural levels of influence for the mutant form that leads to NCL disorder.

Nilotinib: Disrupting the MYC-MAX Heterocomplex.

MYC is a transcription factor crucial for maintaining cellular homeostasis, and its dysregulation is associated with highly aggressive cancers. Despite being considered "undruggable" due to its unstable protein structure, MYC gains stability through its interaction with its partner protein, MAX. The MYC-MAX heterodimer orchestrates the expression of numerous genes that contribute to an oncogenic phenotype. Previous efforts to develop small molecules, disrupting the MYC-MAX interaction, have shown promise in vitro but none have gained clinical approval. Our current computer-aided study utilizes an approach to explore drug repurposing as a strategy for inhibiting the c-MYC-MAX interaction. We have focused on compounds from DrugBank library, including Food and Drug Administration-approved drugs or those under investigation for other medical conditions. First, we identified a potential druggable site on flat interface of the c-MYC protein, which served as the target for virtual screening. Using both activity-based and structure-based screening, we comprehensively assessed the entire DrugBank library. Structure-based virtual screening was performed on AutoDock Vina and Glide docking tools, while activity-based screening was performed on two independent quantitative structure-activity relationship models. We focused on the top 2% of hit molecules from all screening methods. Ultimately, we selected consensus molecules from these screenings-those that exhibited both a stable interaction with c-MYC and superior inhibitory activity against c-MYC-MAX interaction. Among the evaluated molecules, we identified a protein kinase inhibitor (tyrosine kinase inhibitor [TKI]) known as nilotinib as a promising candidate targeting c-MYC-MAX dimer. Molecular dynamic simulations demonstrated a stable interaction between MYC and nilotinib. The interaction with nilotinib led to the stabilization of a region of the MYC protein that is distorted in apo-MYC and is important for MAX binding. Further analysis of differentially expressed gene revealed that nilotinib, uniquely among the tested TKIs, induced a gene expression program in which half of the genes were known to be responsive to c-MYC. Our findings provide the foundation for subsequent in vitro and in vivo investigations aimed at evaluating the efficacy of nilotinib in managing MYC oncogenic activity.

Machine Learning-Based Approach to Identify Inhibitors of Sterol-14-Alpha Demethylase: A Study on Chagas Disease.

Chagas Disease, caused by the parasite Trypanosoma cruzi, remains a significant public health concern, particularly in Latin America. The current standard treatment for Chagas Disease, benznidazole, is associated with various side effects, necessitating the search for alternative therapeutic options. In this study, we aimed to identify potential therapeutics for Chagas Disease through a comprehensive computational analysis. A library of compounds derived from Cananga odorata was screened using a combination of pharmacophore modeling, structure-based screening, and quantitative structure-activity relationship (QSAR) analysis. The pharmacophore model facilitated the efficient screening of the compound library, while the structure-based screening identified hit compounds with promising inhibitory potential against the target enzyme, sterol-14-alpha demethylase. The QSAR model predicted the bioactivity of the hit compounds, revealing one compound to exhibit superior activity compared to benznidazole. Evaluation of the physicochemical, pharmacokinetic, toxicity, and medicinal chemistry properties of the hit compounds indicated their drug-like characteristics, oral bioavailability, ease of synthesis, and reduced toxicity profiles. Overall, our findings present a promising avenue for the discovery of novel therapeutics for Chagas Disease. The identified hit compounds possess favorable drug-like properties and demonstrate potent inhibitory effects against the target enzyme. Further in vitro and in vivo studies are warranted to validate their efficacy and safety profiles.

Structure-based screening of FDA-approved drugs identifies potential histone deacetylase 3 repurposed inhibitor: molecular docking and molecular dynamic simulation approaches.

Histone deacetylase 3 (HDAC3) is a member of the histone deacetylase family that has emerged as a crucial target in the quest for novel therapeutic interventions against various complex diseases, including cancer. The repositioning of FDA-approved drugs presents a promising avenue for the rapid discovery of potential HDAC3 inhibitors. In this study, we performed a structure-based virtual screening of FDA-approved drugs obtained from DrugBank. Candidate hits were selected based on their binding affinities and interactions with HDAC3. These promising hits were then subjected to a comprehensive assessment of their biological properties and drug profiles. Our investigation identified two FDA-approved drugs, Imatinib and Carpipramine, characterized by their exceptional affinity and specificity for the binding pocket of HDAC3. These molecules demonstrated a strong preference for HDAC3 binding site and formed interactions with functionally significant residues within the active site pocket. To gain deeper insights into the binding dynamics, structural stability, and interaction mechanisms, we performed molecular dynamics (MD) simulations spanning 300nanoseconds (ns). The results of MD simulations indicated that Imatinib and Carpipramine stabilized the structure of HDAC3 and induced fewer conformational changes. Taken together, the findings from this study suggest that Imatinib and Carpipramine may offer significant therapeutic potential for treating complex diseases, especially cancer.

Computational Screening and Experimental Validation of Inhibitor Targeting the Complex Formation of Grb14 and Insulin Receptor.

The development of drugs targeting gene products associated with insulin resistance holds the potential to enhance our understanding of type 2 diabetes mellitus (T2DM). The virtual screening, based on a three-dimensional (3D) protein structure, is a potential technique to accelerate the development of molecular target drugs. Among the targets implicated in insulin resistance, the genetic characterization and protein function of Grb14 have been clarified without contradiction. The Grb14 gene displays significant variations in T2DM, and its gene product is known to inhibit the function of the insulin receptor (IR) by directly binding to the tyrosine kinase domain. In the present study, a virtual screening, based on a 3D structure of the IR tyrosine kinase domain (IRβ) in complex with part of Grb14, was conducted to find compounds that can disrupt the complex formation between Grb14 and IRβ. First, ten compounds were selected from 154,118 compounds via hierarchical in silico structure-based drug screening, composed of grid docking-based and genetic algorithm-based programs. The experimental validations suggested that the one compound can affect the blood glucose level. The molecular dynamics simulations and co-immunoprecipitation analysis showed that the compound did not completely suppress the protein-protein interaction between Grb14 and IR, though competitively bound to IR with the tyrosine kinase pseudosubstrate region in Grb14.

TriboNano shield – Scalable manufacturing anti-smog multi-level structured nanofiber air filter with co-enhanced purification performance towards self-powered window screen

Nanofiber air filter has garnered tremendous attention due to large specific surface area, large porosity, highly interconnected aperture channels, etc. However, its unitary interlayer structural construction encounters limitation of filtration performance with a low yield. Here, we architect a triboelectric-induced multi-level interlaminar composite structure-based nanofiber window screen (T-MLNS), manufactured continuously utilizing free surface electrospinning. Subjoined with triboelectric charges (active type), T-MLNS possesses co-enhanced adsorption capacity of aerosols. Additionally, MLNS is constructed with finer fibrous layers for precise filtration and coarser fibrous layers in the middle facilitating airflow passing, under physical filtration mechanisms (passive type). Significantly, three-dimensional theoretical models are innovatively employed with numerical simulation findings that multi-level structures present superb filtration performance than uni-structure ones. In the synergistic effect of the active and passive typed mechanisms, T-MLNS is prolonged service life for precise capture of ultrafine aerosols (Diameter: 0.26 µm) with enhanced filtration efficiency up to 99.9%. The integrated multi-zone structure design creates a pattern-shape fiber mesh, resulting in prominent air permeability (∼100 mm s−1), optical light transmission (> 60%), and robust mechanical properties. This combination of active and passive filtering self-powered window screens offers a unique concept for revolutionising interior air quality in industrialization.

Exploring Thiazolopyridine AV25R: Unraveling of Biological Activities, Selective Anti-Cancer Properties and In Silico Target and Binding Prediction in Hematological Neoplasms.

Thiazolopyridines are a highly relevant class of small molecules, which have previously shown a wide range of biological activities. Besides their anti-tubercular, anti-microbial and anti-viral activities, they also show anti-cancerogenic properties, and play a role as inhibitors of cancer-related proteins. Herein, the biological effects of the thiazolopyridine AV25R, a novel small molecule with unknown biological effects, were characterized. Screening of a set of lymphoma (SUP-T1, SU-DHL-4) and B- acute leukemia cell lines (RS4;11, SEM) revealed highly selective effects of AV25R. The selective anti-proliferative and metabolism-modulating effects were observed in vitro for the B-ALL cell line RS4;11. Further, we were able to detect severe morphological changes and the induction of apoptosis. Gene expression analysis identified a large number of differentially expressed genes after AV25R exposure and significant differentially regulated cancer-related signaling pathways, such as VEGFA-VEGFR2 signaling and the EGF/EGFR pathway. Structure-based pharmacophore screening approaches using in silico modeling identified potential biological AV25R targets. Our results indicate that AV25R binds with several proteins known to regulate cell proliferation and tumor progression, such as FECH, MAP11, EGFR, TGFBR1 and MDM2. The molecular docking analyses indicates that AV25R has a higher binding affinity compared to many of the experimentally validated small molecule inhibitors of these targets. Thus, here we present in vitro and in silico analyses which characterize, for the first time, the molecular acting mechanism of AV25R, including cellular and molecular biologic effects. Additionally, this predicted the target binding of the molecule, revealing a high affinity to cancer-related proteins and, thus, classified AVR25 for targeted intervention approaches.

Design of small molecules for CDK-2 inhibition in colorectal cancer based on substructure search

The global frequency of colorectal cancer motivates extensive drug discovery efforts. CDK2, a key member of the CDK family, has been linked to tumor progression, unregulated cell proliferation, and growth promotion. Water-soluble flavonoids with a fast metabolism called anthocyanins have been shown to have a variety of pharmacological properties, including anti-cancer properties. This study aims to find possible CDK2 inhibitors from Anthocyanin-like molecules. Anthocyanins sourced from PubChem were screened using a virtual screening approach that included a KNIME workflow, QSAR-model, Pharmacophore hypothesis, and a structure-based screening to identify compounds with a better binding affinity and predicted bioactivity compared to the standard, Sorafenib. The top compounds were subjected to a 100 ns MD simulation to confirm their stability at the active site. Compounds 1–5 were shown to have higher binding affinity and bioactivity in this study. These substances interacted with the critical amino acids (LEU 83, ASP 145 and LYS 89) at CDK2's active site. Compared to the reference with a pIC50 value of 6.003 nM, the top compounds listed have superior predicted bioactivity ranging from 6.539 to 6.36 nM. Also, ADMET predictions predicted that Compounds 1–5 were not carcinogenic and not a p-glycoprotein substrate. MD simulation also validated Compound 1's stability at the active site compared to the standard. This study uncovers potential CDK2 inhibitors with good binding affinities, shedding light on their interactions with the target protein. While promising, further in vivo and in vitro investigations are essential to validate the anticancer potential of these compounds. Communicated by Ramaswamy H. Sarma

Small Molecule Inhibition of MAGE-A3 Induces Cell Cycle Arrest and Apoptosis in Multiple Myeloma

Background: The Type I Melanoma Antigen Gene-A3 (MAGE-A3) is commonly expressed in multiple myeloma (MM), a cancer of plasma cells. MAGE-A3 binds to Kap1 to form ubiquitin (Ub) ligase complexes and is associated with inhibition of apoptosis, resistance to chemotherapy, and cell cycle dysregulation. The highly conserved MAGE Homology Domain (MHD) undergoes a conformation change from “closed” to “open” in order to complex with Kap1, activate Ub ligase activity, and bind substrates. RNA interference (RNAi) knockdown of MAGE-A3 in MM cells results in upregulation of the endogenous CDK4/6 inhibitor P21 Cip1 and pro-apoptotic BIM, resulting in cell cycle arrest and intrinsic apoptosis. Knockdown of MAGE-A3 also increased cell death in response to melphalan and panobinostat, but not to bortezomib or cis-platin. These findings lead to the hypothesis that small molecule inhibition (SMI) of MAGE-A3 Ub ligase activity will have therapeutic application in this disease. Methods: We used the Schrodinger suite to perform in silico screening of a custom designed library of compounds using the crystal structure of the MAGE-A3 MHD to identify potential binding molecules that stabilize the closed MHD conformation. Candidates were then screened on human myeloma cell lines (HMCL) by CellTiter-Glo assay to identify compounds that reduced cell viability. Isothermal titration calorimetry was used to identify candidate SMI that bound to the MHD. HMCL were co-incubated with SMI; cell cycling was assessed by BrdU assay and apoptosis by Annexin V staining. Protein expression of p21 Cip1, BIM, and MAGE-A3 was assessed by Western blot. Combinatorial indexes in co-incubation experiments with ergotamine and chemotherapy agents were calculated with the Chou-Talalay method using CompuSyn. Results: Structure-based and biochemical screening nominated ergotamine as a candidate MAGE-A3 SMI. Ergotamine bound to the MAGE-A3 MHD and induced cell cycle arrest and apoptosis in MAGE-A3-expressing human myeloma and lymphoma cell lines and increased expression of pro-apoptotic BIM and p21 Cip1, similar to results with RNAi knockdown. These effects were not observed in negative control MAGE-A3(-) lymphoma cells. Co-incubation of ergotamine with chemotherapy agents melphalan or panobinostat resulted in synergistic killing of MAGE-A3+ HMCL. Ergotamine did not synergize with bortezomib or cis-platin under these conditions. Conclusions: These results support the combined structural and biochemical methods as an efficient means of screening for candidate inhibitors for MAGE-A3. Ergotamine recapitulated the results of RNAi knockdown of MAGE-A3 in cells that express the target, supporting a tool compound for further pharmacologic development. MAGE-A3 SMI have the potential to be a novel class of MM therapy that may be effective alone or in combination with chemotherapy or immune oncology agents. MAGE inhibitors may have broader application in other target-expressing cancers, including lung, melanoma, breast, and ovarian cancers, which are among the most common causes of cancer death.

Fragment databases from screened ligands for drug discovery (FDSL-DD)

Fragment-based drug design (FBDD) is one major drug discovery method employed in computer-aided drug discovery. Due to its inherent limitations, this process experiences long processing times and limited success rates. Here we present a new Fragment Databases from Screened Ligands Drug Design method (FDSL-DD) that intelligently incorporates information about fragment characteristics into a fragment-based design approach to the drug development process. The initial step of the FDSL-DD is the creation of a fragment database from a library of docked, drug-like ligands for a specific target, which deviates from the traditional in silico FBDD strategy, incorporating structure-based design screening techniques to combine the advantages of both approaches. Three different protein targets have been tested in this study to demonstrate the potential of the created fragment library and FDSL-DD. Utilizing the FDSL-DD led to an increase in binding affinity for each protein target. The most substantial increase was exhibited by the ligand designed for TIPE2, with a 3.6 kcalmol-1 difference between the top ligand from the FDSL-DD and top ligand from the high throughput virtual screening (HTVS). Using drug-like ligands in the initial HTVS allows for a greater search of chemical space, with higher efficiency in fragments selection, less grid boxes, and potentially identifying more interactions.

An Exploration of the Inhibitory Mechanism of Rationally Screened Benzofuran-1,3,4-Oxadiazoles and-1,2,4-Triazoles as Inhibitors of NS5B RdRp Hepatitis C Virus through Pharmacoinformatic Approaches.

Benzofuran, 1,3,4-oxadiazole, and 1,2,4-triazole are privileged heterocyclic moieties that display the most promising and wide spectrum of biological activities against a wide variety of diseases. In the current study, benzofuran-1,3,4-oxadiazole BF1-BF7 and benzofuran-1,2,4-triazole compounds BF8-BF15 were tested against HCV NS5B RNA-dependent RNA polymerase (RdRp) utilizing structure-based screening via a computer-aided drug design (CADD) approach. A molecular docking approach was applied to evaluate the binding potential of benzofuran-appended 1,3,4-oxadiazole and 1,2,4-triazole BF1-BF15 molecules. Benzofuran-1,3,4-oxadiazole scaffolds BF1-BF7 showed lesser binding affinities (-12.63 to -14.04 Kcal/mol) than benzofuran-1,2,4-triazole scaffolds BF8-BF15 (-14.11 to -16.09 Kcal/mol) against the HCV NS5B enzyme. Molecular docking studies revealed the excellent binding affinity scores exhibited by benzofuran-1,2,4-triazole structural motifs BF-9 (-16.09 Kcal/mol), BF-12 (-15.75 Kcal/mol), and BF-13 (-15.82 Kcal/mol), respectively, which were comparatively better than benzofuran-based HCV NS5B inhibitors' standard reference drug Nesbuvir (-15.42 Kcal/mol). A molecular dynamics simulation assay was also conducted to obtain valuable insights about the enzyme-compounds interaction profile and structural stability, which indicated the strong intermolecular energies of the BF-9+NS5B complex and the BF-12+NS5B complex as per the MM-PBSA method, while the BF-12+NS5B complex was the most stable system as per the MM-GBSA calculation. The drug-likeness and ADMET studies of all the benzofuran-1,2,4-triazole derivatives BF8-BF15 revealed that these compounds possessed good medicinal chemistry profiles in agreement with all the evaluated parameters for being drugs. The molecular docking affinity scores, MM-PBSA/MM-GBSA and MD-simulation stability analysis, drug-likeness profiling, and ADMET study assessment indicated that N-4-fluorophenyl-S-linked benzofuran-1,2,4-triazole BF-12 could be a future promising anti-HCV NS5B RdRp inhibitor therapeutic drug candidate that has a structural agreement with the Nesbuvir standard reference drug.

Virtual Insights into Natural Compounds as Potential 5α-Reductase Type II Inhibitors: A Structure-Based Screening and Molecular Dynamics Simulation Study.

Androgenic alopecia (AGA) is a dermatological disease with psychosocial consequences for those who experience hair loss. AGA is linked to an increase in androgen levels caused by an excess of dihydrotestosterone in blood capillaries produced from testosterone by 5α-reductase type II (5αR2), which is expressed in scalp hair follicles; 5αR2 activity and dihydrotestosterone levels are elevated in balding scalps. The diverse health benefits of flavonoids have been widely reported in epidemiological studies, and research interest continues to increase. In this study, a virtual screening approach was used to identify compounds that interact with active site residues of 5αR2 by screening a library containing 241 flavonoid compounds. Here, we report two potent flavonoid compounds, eriocitrin and silymarin, that interacted strongly with 5αR2, with binding energies of -12.1 and -11.7 kcal/mol, respectively, which were more significant than those of the control, finasteride (-11.2 kcal/mol). Molecular dynamic simulations (200 ns) were used to optimize the interactions between compounds and 5αR2 and revealed that the interaction of eriocitrin and silymarin with 5αR2 was stable. The study shows that eriocitrin and silymarin provide developmental bases for novel 5αR2 inhibitors for the management of AGA.

Prediction of molecular interaction of Phosphodiesterase 10A inhibition by natural compounds: insights from structure-based screening and molecular dynamics simulations

Phosphodiesterase 10 A (PDE10A) is an enzyme that regulates cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in the brain, particularly in the striatum, which plays a critical role in movement control and reward processing. Inhibition of PDE10A can increase cAMP and cGMP levels, improving neuronal signaling and reducing symptoms of neuropsychiatric disorders such as schizophrenia, Huntington’s disease, and Parkinson’s disease. In this study, a structure-based virtual screening was conducted to identify potential anti-neuropsychiatric disorders compounds from phytoconstituents in the IMPPAT database. The ligands were docked against PDE10A, resulting in 40 compounds with appreciable docking scores. These 40 compounds underwent further ADMET predictions and drug likeliness, resulting in five potential compounds. Finally, based on the specific interactions, two compounds (Colladonin and Isopongachromene), were subjected to molecular dynamics (MD) simulation and MM-PBSA studies. The MM-PBSA analysis validated and captured the intermolecular interactions, indicating that Colladonin and Isopongachromene had appreciable binding affinities of −155.60 kJ.mol−1 and −108.28 kJ.mol−1, respectively and were promising candidates against neuropsychiatric disorders, targeting PDE10A. Overall, this study provides insight into the potential of PDE10A inhibitors as therapeutic agents for treating neuropsychiatric disorders, and Colladonin and Isopongachromene are promising compounds for further development. Communicated by Ramaswamy H. Sarma

In Silico Study of Potential Small Molecule TIPE2 Inhibitors for the Treatment of Cancer

Context: Chronic inflammation has been linked to cancer since the 19th century. Tumor growth is supported by the proangiogenic factors that chronic inflammation requires. Polarized leukocytes initiate these angiogenic and tumorigenic factors. TIPE2, a transport protein, manages the cytoskeletal rearrangement that gives a polarized leukocyte its motility. Inhibition of this protein could lead to a therapeutic option for solid tumor cancers; however, no such inhibitors have been developed so far due to the large cavity size of the TIPE2 protein. Here we have examined possible small molecule inhibitors by combining structure-based and fragment-based drug design approaches. The highest binding ligands were complexed with the protein, and fragment libraries were docked with the complex with the intention of linking the hit compounds and fragments to design a more potent ligand. Three hit compounds were identified by in silico structure-based screening and a linked compound, C2–F14, of excellent binding affinity, was identified by linking fragments to the hit compounds. C2–F14 demonstrates good binding stability in molecular dynamic simulations and great predicted ADME properties. Methods: High throughput molecular docking calculations of mass libraries were performed using AutoDock Vina 1.1.2. Molecular docking of individual ligands was performed using AutoDock Vina with PyRx. Ligand libraries were prepared using OpenBabel, linked ligands were prepared using Avogadro. The protein was prepared using AutoDockTools-1.5.6. Protein-ligand complexes were visualized with PyMOL. Two- and three-dimensional representations of protein–ligand interactions were plotted with BIOVIA Discovery Studio Visualizer. In silico absorption, distribution, metabolism, and excretion (ADME) properties were calculated using SwissADME. Molecular dynamics simulations were conducted with GROMACS.

Mechanisms of Nelumbinis folium targeting PPARγ for weight management: A molecular docking and molecular dynamics simulations study

The lotus leaf, Nelumbinis folium (NF), has frequently appeared in obesity clinical trials as an intervention to promote weight loss and improve metabolic profiles. However, the molecular mechanisms by which it interacts with important obesity targets and pathways, such as the peroxisome proliferator-activated receptor gamma (PPARγ) within the PPAR signalling pathway, were not well understood. This study aims to screen for candidate compounds from NF with desirable pharmacokinetic properties and examine their binding feasibility at the PPARγ ligand-binding domain (LBD). Ligand- and structure-based screening of NF compounds were performed, and a consensus approach has been applied to identify druggable candidates. By examining the pharmacokinetic profiles, a large proportion of NF compounds exhibited favourable drug-likeness and oral bioavailability properties. Furthermore, the binding affinity scores and poses provided new insights on the distinctive binding behaviours of NF compounds at the LBD of PPARγ in its inactive form. Several NF compounds could bind strongly to PPARγ at sub-pockets where partial agonists and antagonists were found to bind and may induce conformational changes that influence co-repressor binding, trans-repression, and gene expression inhibition. Subsequent molecular dynamics simulations of a candidate compound (NF129 narcissin) bound to PPARγ revealed conformational stability, residue fluctuation, and binding behaviours comparable to that of the known inhibitor, SR1664. Therefore, it can be proposed that narcissin exhibits characteristics of a PPARγ antagonist. Further experimental validation to support the development of NF129 as a future anti-obesity agent is warranted.

Repurposing existing drugs for monkeypox: applications of virtual screening methods

BackgroundMonkeypox is endemic to African region and has become of Global concern recently due to its outbreaks in non-endemic countries. Although, the disease was first recorded in 1970, no monkeypox specific drug or vaccine exists as of now.MethodsWe applied drug repositioning method, testing effectiveness of currently approved drugs against emerging disease, as one of the most affordable approaches for discovering novel treatment measures. Techniques such as virtual ligand-based and structure-based screening were applied to identify potential drug candidates against monkeypox.ResultsWe narrowed down our results to 6 antiviral and 20 anti-tumor drugs that exhibit theoretically higher potency than tecovirimat, the currently approved drug for monkeypox disease.ConclusionsOur results indicated that selected drug compounds displayed strong binding affinity for p37 receptor of monkeypox virus and therefore can potentially be used in future studies to confirm their effectiveness against the disease.

Substrate binding and inhibition of the anion exchanger 1 transporter.

Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO2 transport between lungs and tissues. Previous studies characterized its role in erythrocyte structure and provided insight into transport regulation. However, key questions remain regarding substrate binding and transport, mechanisms of drug inhibition and modulation by membrane components. Here we present seven cryo-EM structures in apo, bicarbonate-bound and inhibitor-bound states. These, combined with uptake and computational studies, reveal important molecular features of substrate recognition and transport, and illuminate sterol binding sites, to elucidate distinct inhibitory mechanisms of research chemicals and prescription drugs. We further probe the substrate binding site via structure-based ligand screening, identifying an AE1 inhibitor. Together, our findings provide insight into mechanisms of solute carrier transport and inhibition.

Structure-based virtual screening of new antitumor natural berberines: Bioactivity against pancreas cancer by HIF1 inhibition effect

Despite medical and technological advances to contain the proliferation of pancreatic cancer, many diagnoses are late due to the high specificity of this type of cancer. Because it is asymptomatic cancer until the most advanced or terminal state, the efficiency of therapeutic actions can be reduced. HIF-1α is the factor that regulates crucial genes involved in tumor proliferation and metastasis. In this study, a virtual structure-based screening was carried out to evaluate the alignment between pharmacokinetics and pharmacodynamics against the anti-cancer mechanism of the pancreas via HIF-1α of new derivatives of the natural product berberine, a natural alkaloid based on protic isoquinoline whose antitumor effect is reported in the literature. Here, a multiparametric optimization system is used to estimate, quantitatively and topologically, the alignment between the pharmacokinetic attributes of these analogs, where it was possible to observe that the less lipophilic analogs, that is, the 1a-b derivatives, showed better ADME viability. Furthermore, the substitution of alkyl bromide promotes an inductive electron-withdrawing effect that increases the probability of demethylation in analog 1b and reduces the number of O-dealkylation sites, increasing the metabolic stability of the compound. The results of molecular docking suggest that the ligands with better viability of ADME also present a great affinity and specificity for the HIF-1α receptor, mainly in interactions in common with the residue of Thr 196, present in the binding site of the OGA inhibitor, constituting promising ligands in the treatment of pancreatic cancer.

Structure-based screening of orally bioavailable VEGFR2 inhibitors that abrogate tumor growth by inhibiting angiogenesis

Structure-based screening of orally bioavailable VEGFR2 inhibitors that abrogate tumor growth by inhibiting angiogenesis

Identification of a small chemical as a lysosomal calcium mobilizer and characterization of its ability to inhibit autophagy and viral infection.

We previously identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as one of the cyclic adenosine diphosphoribose (cADPR)'s binding proteins and found that GAPDH participates in cADPR-mediated Ca2+ release from endoplasmic reticulum via ryanodine receptors (RyRs). Here, we aimed to chemically synthesise and pharmacologically characterise novel cADPR analogues. Based on the simulated cADPR-GAPDH complex structure, we performed the structure-based drug screening, identified several small chemicals with high docking scores to cADPR's binding pocket in GAPDH and showed that two of these compounds, C244 and C346, are potential cADPR antagonists. We further synthesised several analogues of C346 and found that its analogue, G42, also mobilised Ca2+ release from lysosomes. G42 alkalised lysosomal pH and inhibited autophagosome-lysosome fusion. Moreover, G42 markedly inhibited Zika virus (ZIKV, a flavivirus) or murine hepatitis virus (MHV, a β-coronavirus) infections of host cells. These results suggest that G42 inhibits virus infection, likely by triggering lysosomal Ca2+ mobilisation and inhibiting autophagy.