In Silico Pharmacology

There is an urgent need to discover and develop new drugs to combat Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) in humans. In recent years, there has been a renewed interest in the discovery of new anti-TB agents from natural sources. In the present investigation, molecular docking studies were carried out on two ellagic acid derivatives, namely pteleoellagic acid (1) isolated from Ludwigia adscendens, and 3,3′-di-O-methyl ellagic acid 4-O-α-rhamnopyranoside (2) isolated from Trewia nudiflora, to investigate their binding to two enzymes involved in M. tuberculosis cell wall biogenesis, namely 2-trans-enoyl-ACP reductase (InhA) and β-ketoacyl-ACP reductase (MabA), and to pantothenate kinase (PanK type I) involved in the biosynthesis of coenzyme A, essential for the growth of M. tuberculosis. Molecular docking experiments were performed using AutoDock Vina. The crystal structures of InhA, MabA and PanK were retrieved from the RCSB Protein Data Bank (PDB). Isonicotinic-acyl-NADH for InhA and MabA, and triazole inhibitory compound for PanK, were used as references. Pteleoellagic acid showed a high docking score, estimated binding free energy of −9.4 kcal/mol, for the MabA enzyme comparable to the reference compound isonicotinic-acyl-NADH. Knowledge on the molecular interactions of ellagic acid derivatives with essential M. tuberculosis targets could prove a useful tool for the design and development of future anti-TB drugs.

Cardiovascular diseases are the primary factor for increased mortality rates around the world. Atherosclerosis brought on by high serum cholesterol can result in coronary heart disease (CHD). The risk of CHD is markedly reduced by lowering serum cholesterol levels. Scientists across the world are inventing new treatment regimens for lowering blood lipid levels. In this work, we repurposed the already established drugs, i.e., cyclizine derivatives as antihyperlipidemic agents. The repurposing was done based on the similarity of the selected cyclizine derivatives with the already established antihyperlipidemic drug, fenofibrate. Computational studies were performed and the 16 cyclizine derivatives docked against PPAR. alpha scored higher than fenofibrate. Lifarizine and medibazine outperform fenofibrate inmmgbsa. Fenofibrate, etodroxizine, meclizine, and cinnarizine had similar mmgbsa scores. The ADME properties of these compounds were performed and from that etodroxizine and levocetirizine were found to have better properties. The computational studies were performed using the Schrodinger software, maestro 12.8. The “Protein Preparation Wizard” module in the Maestro panel was used to create the protein structure and OPLS4 force field was used for energy minimization. The maestro builder panel’s “Ligprep”, “Receptor Grid Generation” and “Ligand Docking” modules were then used to prepare ligands, receptor grids and to perform docking respectively. MMGBSA was performed on the “prime MMGBSA” segment. Using the “Qikprop” setting in the maestro panel, a number of ADMET properties were predicted, and the program was run in default mode using vsgb as the solvation model.

The emergence of resistant bacteria strains against traditional antibiotics and treatments increases each year. Doderlin is a cationic and amphiphilic peptide active against gram-positive, negative and yeast stains. The aim of the present work was prospect potentials receptors associated of antimicrobial activity of Doderlin using in silico bioinformatics tools. To search for potential targets of Doderlin, PharmMapper software was used. Molecular docking between Doderlin and the receptor was performed by PatchDock. Additional interaction and ligand site prediction for each receptor was performed by I-TASSER software. Those PDB Id, 1XDJ (score: 11,746), 1JMH (score: 11,046), 1YR3 (score: 10,578), 1NG3 (score: 10,082) showed highest dock score. Doderlin was found to predicted/real sites co-localize with 1XDJ and 1JMH, enzymes accountable for nitrogenic bases synthesis. The resulting receptor bioprospecting is highly correlated and suggests that Doderlin might act by interfering with DNA metabolism/production of bacteria, altering microorganism homeostasis and growth impairment.

The reader proteins like bromodomains have recently gained increased attentions in the area of epigenetic drug discovery, as they are the potent regulators in gene transcription process. Among the other bromodomains, cAMP response element-binding protein (CREB) binding protein or CREBBP bomodomain involved in various cancer progressions and therefore, efforts to develop specific inhibitors of CREBBP bomodomain are of clinical value. In this study, we tried to identify selective CREBBP bromodomain inhibitor, which was accomplished by using molecular docking, free energy calculation and molecular dynamics (MD) simulation studies, considering a series of naphthyl based compounds. The docking procedure was validated by comparing root mean square deviations (RMSDs) of crystallographic complex to docked complex. Favorable electrostatic interactions with the Arg1173 side chain were considered to attain selectivity for CREBBP bromodomain over other human bromodomain subfamilies. We found that naphthyl-based compounds have greater binding affinities towards the CREBBP bromodomain, and formed non-bonded interactions with various side chain residues that are important for bromodomain inhibition. From detailed investigation by induced fit docking, compound 31 was found to have favorable electrostatic interactions with the Arg1173 side chain by forming conventional hydrogen bonds. This result was further confirmed by analyzing hydrogen bond occupancy and bonding distance during the molecular dynamics simulation. We believe that these findings offer useful insight for the designing of target specific new bromodomain inhibitor and also promote further structure guided synthesis of analogues for identification of potent CREBBP bromodomain inhibitors as well as detailed in vitro and in vivo analyses.

Diabesity là một vấn đề sức khỏe toàn cầu nghiêm trọng, và ghrelin O-acyltransferase (GOAT) đóng vai trò là một mục tiêu quan trọng trong việc phát triển các chất ức chế mới cho căn bệnh này. Công trình hiện tại làm nổi bật một nghiên cứu QSAR chi tiết sử dụng phần mềm QSARINS, cung cấp một phương trình mô hình xuất sắc sử dụng các mô tả đặc trưng. Ở đây, phương trình mô hình tốt nhất được phát triển có hai biến số, cụ thể là MLFER_E và XlogP, với các tham số thống kê R2 = 0.8433, LOF = 0.0793, CCCtr = 0.915, Q2LOO = 0.8303, Q2LMO = 0.8275, CCCcv = 0.9081, R2ext = 0.7712, và CCCext = 0.8668. Một sự tương quan cao giữa các fragment cấu trúc chính với hoạt tính đã được xác nhận bởi mô hình QSAR phát triển. Hơn nữa, mô hình docking phân tử đã giúp chúng tôi xác định các tương tác liên kết. Ba mươi bốn phân tử mới với hoạt tính sinh học được dự đoán tốt hơn (pIC50) đã được thiết kế. Năng lượng liên kết của bốn hợp chất cho thấy hoạt tính liên kết cao hơn trong protein màng (PDB Id: 6BUG). Mô phỏng động lực học phân tử đã xác lập độ ổn định của phức hợp protein-ligand trong 100 ns. Phân tích DFT và độc tính ADME cũng xác nhận các tính chất giống thuốc của chúng. Dựa trên những phát hiện của chúng tôi, chúng tôi báo cáo rằng các dẫn xuất oxadiazolo pyridine mới này dẫn đến phát triển những ứng cử viên mạnh cho việc phát triển tiếp. METTL3 trung gian HOTAIRM1 thúc đẩy mô phỏng mạch máu trong glioma thông qua việc điều chỉnh biểu hiện IGFBP2. Biểu hiện METTL3 cao trong tế bào và mô glioma làm ổn định và tăng cường sự biểu hiện HOTAIRM1. HOTAIRM1 này sau đó tương tác với IGFBP2 và làm tăng tính ác tính của tế bào glioma và sự hình thành mô phỏng mạch máu (VM), do đó cung cấp một hướng đi mới cho liệu pháp điều trị glioma.

Adenosine receptors (ARs) belong to the G protein-coupled receptors (GCPRs) family. The recent release of X-ray structures of the human A2A AR (h A2A AR ) in complex with agonists and antagonists has increased the application of structure-based drug design approaches to this class of receptors. Among them, homology modeling represents the method of choice to gather structural information on the other receptor subtypes, namely A1, A2B, and A3 ARs. With the aim of helping users in the selection of either a template to build its own models or ARs homology models publicly available on our platform, we implemented our web-resource dedicated to ARs, Adenosiland, with the “Best Template Searching” facility. This tool is freely accessible at the following web address: http://mms.dsfarm.unipd.it/Adenosiland/ligand.php . The template suggestions and homology models provided by the “Best Template Searching” tool are guided by the similarity of a query structure (putative or known ARs ligand) with all ligands co-crystallized with hA2A AR subtype. The tool computes several similarity indexes and sort the outcoming results according to the index selected by the user. We have implemented our web-resource dedicated to ARs Adenosiland with the “Best Template Searching” facility, a tool to guide template and models selection for hARs modelling. The underlying idea of our new facility, that is the selection of a template (or models built upon a template) whose co-crystallized ligand shares the highest similarity with the query structure, can be easily extended to other GPCRs.

The signaling molecules TNF-α, AP-1, and NF-κB act to integrate multiple stress signals into a series of diverse antiproliferative responses. Disruption of these processes can promote tumor progression and chemoresistance. Naturally occurring plant derived compounds are considered as attractive candidates for cancer treatment and prevention. Phytoconstituents can control and modify various biological activities by interacting with molecules involved in concerned signaling pathways. The aim of this study was to find binding conformations between phytoconstituents and these signaling molecules responsible for multiple stress signals of UVB induced photodamage. Induced fit docking was carried out for understanding the binding interactions of pantothenic acid (vitamin B5); 3,4,5-trihydroxy benzoic acid (gallic acid); madecassic acid and hexadecanoic acid, ethyl ester (palmitic acid) with TNF-α, AP-1, and NF-κB. Favorable binding conformations between these signaling molecules and the four phytoconstituents were observed. A number of poses were generated to evaluate the binding conformations and common interacting residues between the ligands and proteins. Among them, the best ligands against TNF-α, AP-1, and NF-κB are reported. The present investigation strongly suggests the probable use of these flavonoids for the amelioration of UVB induced photodamage.

Bidens pilosa L. has been traditionally used as an anti-diabetic herbal medicine; however, its mechanism of action remains elusive. In this study, the potential role of B. pilosa compounds on alpha-amylase inhibition and regulation of multiple pathways was investigated via computational and experimental studies. The phytocompounds were retrieved from plant databases and published literature. The druggability profile of these compounds was predicted using MolSoft. The probable targets of these phytocompounds were predicted using BindingDB (similarity index ≥ 0.7). Further, compound-gene set-pathway and functional enrichment analysis were performed using STRING and KEGG pathway databases. The network between compound-protein-pathway was constructed using Cytoscape. Molecular docking was performed using AutoDock Vina, executed through the POAP pipeline. The stability of the best docked complex was subjected to all-atom molecular dynamics (MD) simulation for 100 ns to investigate their structural stabilities and intermolecular interactions using GROMACS software. Finally, B. pilosa hydroalcoholic extract was subjected to LC–MS and tested for dose- and time-dependent alpha-amylase inhibitory activity. Out of 31 bioactive compounds, 13 were predicted to modulate the human pancreatic alpha-amylase (AMY2A) and 12 pathways associated with diabetes mellitus. PI3K-Akt signaling pathway (hsa04151) scored the lowest false discovery rate by triggering 15 genes. Further intermolecular interaction analysis of the docked complex revealed that Brassidin had the highest active site interaction and lowest binding energy compared to standard acarbose, and MD reveals the formation of a stable complex throughout 100 ns production run. LC–MS analysis revealed the presence of 13 compounds (targeting AMY2A) in B. pilosa hydroalcoholic extract, which showed potent AMY2A inhibition by in vitro studies that corroborate in silico findings for its anti-diabetic activity. Based on these findings, enriched fractions/pure compounds inhibitory activity that can be performed in future for drug discovery.