Docking and ADMET prediction of few GSK-3 inhibitors divulges 6-bromoindirubin-3-oxime as a potential inhibitor

GSK-3 is a member of cellular kinases with diversified functions such as cellular differentiation, metabolic signaling, neuronal functions and apoptosis. It has been validated as an important therapeutic target in Alzheimer’s disease and type 2 diabetes. Few molecules targeting GSK-3 are currently in clinical trials. In this study, we have compared certain docking and computational ADME (Absorption, Distribution, Metabolism, Excretion) parameters of a few GSK-3 targeted ligands (Indirubin, Hymenialdisine, Meridianins, 6-bromoindirubin-3-oxime) against two control molecules (Tideglusib and LY-2090314) to derive and analyze the basic drug-like properties of the test compounds. Docking between the GSK-3 and various ligands was done using AutoDock while ADME parameters were derived from ADMET server PreADMET and admetSAR. Various docked images were retrieved from docking, indicating the docking sites in the target protein. Out of four compounds tested, 6-bromoindirubin-3-oxime (6-BIO) was found as the best docking and ADME parameters, followed by Hymenialdisine (HMD). The LigPlot interaction results show two residues Leu (188) and Thr (138) to be common at the interaction site. The LD₅₀ of 6-BIO is better than one of the control ligands while very similar to the other. Some of the parameters were very similar to the control ligands, thus, making it a suitable candidate among the test ligands. From this in-silico study, we concluded that 6-BIO is a potent drug candidate which could be further tested in vitro and in vivo to establish a drug molecule. Since, 6-BIO is a chemically modified form of the basic molecule Indirubin, we can hypothesize that certain other modified indirubins could be tested as GSK-3 targeted ligands.     

Exploring the binding sites of Staphylococcus aureus phenylalanine tRNA synthetase: A homology model approach

Increased resistance of MRSA (multidrug resistance Staphylococcus aureus) to anti-infective drugs is a threat to global health necessitating the development of anti-infectives with novel mechanisms of action. Phenylalanine tRNA synthetase (PheRS) is a unique enzyme of the aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes for protein biosynthesis. PheRS is an (αb)₂ tetrameric enzyme composed of two alpha subunits (PheS) and two larger beta subunits (PheT). Our potential target in the drug development for the treatment of MRSA infections is the phenylalanine tRNA synthetase alpha subunit that contains the binding site for the natural substrate. There is no crystal structure available for S. aureus PheRS, therefore comparative structure modeling is required to establish a putative 3D structure for the required enzyme enabling development of new inhibitors with greater selectivity. The S. aureus PheRS alpha subunit homology model was constructed using Molecular Operating Environment (MOE) software. Staphylococcus haemolyticus PheRS was the main template while Thermus thermophilus PheRS was utilised to predict the enzyme binding with tRNA^phe. The model has been evaluated and compared with the main template through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). The query protein active site was predicted from its sequence using a conservation analysis tool. Docking suitable ligands using MOE into the constructed model were used to assess the predicted active sites. The docked ligands involved the PheRS natural substrate (phenylalanine), phenylalanyl-adenylate and several described S. aureus PheRS inhibitors.     

In silico approaches and proportional odds model towards identifying selective ADAM17 inhibitors from anti-inflammatory natural molecules

ADAM metallopeptidase domain 17 (ADAM17) is an attractive target for the development of new anti-inflammatory drugs. We aimed to identify selective inhibitors of ADAM17 against matrix metalloproteinase enzymes (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, and MMP-16) which have substantial structural similarity. Target proteins were docked with 29 anti-inflammatory natural molecule ligands and a known selective inhibitor IK682. The ligands were screened based on Lipinski rules, interaction with the ADAM17 active site cavity, and then ranked using the proportional odds model multinomial logistic regression. Silymarin was the most selective inhibitor of ADAM17 exhibiting H-bonding with Glu 406, Gly 349, Glu 398, Asn 447, Tyr 433, and Lys 432. Molecular dynamics simulations were carried out for 10 ns. The root mean square deviation (RMSD), root mean squared fluctuations (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), and H-bonding indicated the induced metastability. A comparison of the principal component analysis revealed that the silymarin complex also explored lesser region compared to IK682 complex. A control study on ADAM17 protein (2OI0) is included. These observations present silymarin (widely present in plants such as milk thistle (Silybum maianum), wild artichokes (Cynara cardunculus), turmeric (Curcuma longa) roots, coriander (Coriandrum sativum) seeds, etc.) as a promising natural template for development of ADAM17 selective drugs.     

Designing of multi-targeted molecules using combination of molecular screening and in silico drug cardiotoxicity prediction approaches

We have previously investigated and reported a set of phenol- and indole-based derivatives at the binding pockets of carbonic anhydrase isoenzymes using in silico and in vitro analyses. In this study, we extended our analysis to explore multi-targeted molecules from this set of compounds. Thus, 26 ligands are screened at the binding sites of 229 proteins from 5 main enzyme family classes using molecular docking algorithms. Derived docking scores are compared with reported results of ligands at carbonic anhydrase I and II isoenzymes. Results showed potency of multi-targeted drugs of a few compounds from investigated ligand set. These promising ligands are then tested in silico for their cardiotoxicity risks. Results of this work can be used to improve the desired effects of these compounds by molecular engineering studies. In addition these results may lead to further investigation of studied molecules by medicinal chemists to explore different therapeutic aims.     

In silico investigation of medicinal spectrum of imidazo-azines from the perspective of multitarget screening against malaria,tuberculosis and Chagas disease

A chemical database of 30 representative imidazo-azines was built and screened against important tropical disease targets by computational docking. After three rounds of screening, an interaction profile was generated and analyzed. On the basis of binding energy and ligand efficiency, it was concluded that in general, imidazo-azine scaffold has a potential of being selective and simultaneous inhibitor against the five receptors Pf-dihydrofolate reductase, Pf-enoyl acyl carrier protein reductase, Pf-protein kinase 7, Mt-pantothenate synthetase and Mt-thymidine monophosphate kinase. Interestingly, two compounds 2-(4-chlorophenyl)-N-cyclohexyl-6-methylH-imidazo[1,2-a]pyridine-3-amine (MCL011) and N-cyclohexyl-2-(4-methoxyphenyl)-6-methylH-imidazo[1,2-a]pyridine-3-amine (MCL017) showed highest binding energy against four targets namely Pf-dihydrofolate reductase, Pf-enoyl acyl carrier protein reductase, Pf-protein kinase 7 and Mt-pantothenate synthetase. Eventually, in order to improve the decision making and success rate in actual efficacy evaluations other criteria such as lead-likeness were envisaged.     

Design of fructose-2,6-bisphosphatase inhibitors: a novel virtual screening approach

Fructose-2,6-bisphosphatase (FBPase-2) is a switch between gluconeogenesis and glycolysis in the hepatic cells. The structural features required for inhibitory activity of FBPase-2 were unidentified; no leads are available for inhibiting this important enzyme. In this paper pharmacophore mapping, molecular docking methods were employed in a virtual screening strategy to identify leads for FBPase-2. A receptor based pharmacophore map was modeled which comprised of important interactions as observed in co-crystal of rat liver isozyme with the product inhibitor fructose-6-phosphate. The pharmacophore model was validated against two databases of best docked structural analogues of fructose-2,6-bisphosphate and fructose-6-phosphate. The query generated was submitted for flexible search of ligands in chemical databases, namely LeadQuest, Maybridge and NCI. The hits obtained were further screened by molecular docking using FlexX.     

In silico design: Extended molecular dynamic simulations of a new series of dually acting inhibitors against EGFR and HER2

Based on the hit structures that have been identified in our previous studies against EGFR and HER2, new potential inhibitors that share the same scaffold of the hit structures are designed and screened in silico. Insights into understanding the potential inhibitory effect of the new inhibitors against both EGFR and HER2 receptors is obtained using extended molecular dynamics (MD) simulations and different scoring techniques. The binding mechanisms and dynamics are detailed with respect to two approved inhibitors against EGFR (lapatinib) and HER2 (SYR127063). The best scoring inhibitor (T9) is chosen for additional in silico investigation against both the wild-type and T790M mutant strain of EGFR and the wild-type HER2. The results reveal that certain substitution patterns increase the stability and assure stronger binding and higher H-bond occupancy of the conserved water molecule that is commonly observed with kinase crystal structures. Furthermore, the new inhibitor (T9) forms stable interactions with the mutant strain as a direct consequence of the enhanced ability to form additional hydrogen bonding interactions with binding site residues.     

Homology modeling of T. cruzi and L. major NADH-dependent fumarate reductases: Ligand docking,molecular dynamics validation,and insights on their binding modes

Leishmania major and Trypanosoma cruzi are the main causes of leishmaniasis and Chagas disease, two endemic parasitosis identified as neglected diseases by the World Health Organization. Fumarate reductase (FR) is a central enzyme in the conversion of fumarate to succinate, an energy releasing path essential for the survival of these protozoans which is also absent in their mammalian hosts. FR can thus be considered as a good candidate for targeting specific inhibition by new drugs designed against L. major and T. cruzi. The lack of tertiary structures available for LmFR and TcFR has limited until now the possibility of performing structure-based drug design. Here we used homology modeling combined with enzyme-cofactor docking to propose tertiary structures for NADH-dependent LmFR and TcFR using an homologous X-ray crystallographic structure of flavine-adenine dinucleotide (FAD) dependent FR from Shewanella frigidimarina (PDB ID: 1QO8) as template. These models were refined and stabilized with/without substrate in the active site using classical molecular dynamics simulations under quasi-physiological conditions. Structural features relevant for understanding the mechanism of action of the enzyme were also analyzed, with special attention to the hydrogen bond network involving the cofactor and water molecules present at the binding sites. A small set of compounds previously synthesized and assayed for their inhibitory capacity against TcFR ([M(mpo)₂] metal complexes with M = Pt^II, Pd^II and V^IVO and mpo = 2-mercaptopyridine N-oxide) and LmFR (licochalcone A) were screened by protein–ligand docking using the NADH-LmFR and NADH-TcFR models here proposed and validated, gaining insight into their binding modes in each enzyme.     

In silico identification of novel inhibitors against Plasmodium falciparum dihydroorate dehydrogenase

Plasmodium falciparum causes the most fatal form of malaria and accounts for over 1 million deaths annually, yet currently used drug therapies are compromised by resistance. The malaria parasite cannot salvage pyrimidines and relies on de novo biosynthesis for survival. The enzyme dihydrooratate dehydrogenase (DHODH), a mitochondrial flavoenzyme, catalyzes the rate-limiting step of this pathway and is therefore an attractive anti-malarial chemotherapeutic target. In an effort to design new and potential anti-malarials, structure-based pharmacophore mapping, molecular docking, binding energy calculations and binding affinity predictions were employed in a virtual screening strategy to design new and potent P. falciparum dihydrooratate dehydrogenase (PfDHODH) inhibitors. A structure-based pharmacophore model was generated which consist of important interactions as observed in co-crystal of PfDHODH enzyme. The developed model was used to retrieve molecules from ChemBridge database, a freely available commercial database. A total of 87 molecules mapped on the modeled pharmacophore from the database. The retrieved hits were further screened by docking simulation, binding energy calculations and biding affinity predictions using genetic optimization for ligand docking (GOLD) and MOE. Based on these results, finally 26 chemo-types molecules were predicted as new, potential and structurally diverse PfDHODH inhibitors.     

Novel flavonol analogues as potential inhibitors of JMJD3 histone demethylase—A study based on molecular modelling

Epigenetic modulation of gene expression has drawn enormous attention among researchers globally in the present scenario. Since their discovery, Jmj-C histone demethylases were identified as useful markers in understanding the role of epigenetics in inflammatory conditions and in cancer as well. This has created arousal of interest in search of suitable candidates. Potential inhibitors from various other scaffolds such as hydroxyquinolines, hydroxamic acids and triazolopyridines have already been identified and reported. In this direction, our present study attempts to target one of the important members of the family- namely JMJD3 (also known as KDM6B), that plays a pivotal role in inflammatory and immune reactions. Using molecular modeling approaches, myricetin analogues were identified as promising inhibitors of JMJD3. Extensive literature review showed myricetin as the most promising flavonol inhibitor for this enzyme. It served as a prototype for our study and modification of it’s scaffold led to generation of analogues. The ZINC database was used as a repository for natural compounds and their analogues. Using similarity search options, 65 analogues of myricetin were identified and screened against JMJD3 (PDB ID: 4ASK), using the high throughput virtual screening and ligand docking tools in Maestro Molecular Modeling platform (version 10.5) from Schrödinger, LLC. 8 analogues out of 65 were identified as the most appropriate candidates which gave the best pose in ligand docking. Their binding mode and energy calculations were analysed using induced fit docking (IFD) and prime-MMGBSA tool, respectively. Thus, our findings highlight the most promising analogues of myricetin with comparable binding affinity as well as binding energy than their counterparts that could be taken for further optimisation as inhibitors of JMJD3 in both in vitro and in vivo screening studies.     

Structure-based design of hERG-neutral antihypertensive oxazalone and imidazolone derivatives

Angiotensin II receptor type 1 (AT1) antagonists are the most recent drug class against hypertension. Recently first crystal structure of AT1 receptor is deposited to the protein data bank (PDB ID: 4YAY). In this work, several molecular screening methods such as molecular docking and de novo design studies were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor. A database consisting of 3500-fragments were used to enumerate de novo designed imidazolone and oxazolone derivatives and hereby more than 50000 novel small molecules were generated. These derivatives were then used in high throughput virtual screening simulations (Glide/HTVS) to find potent hit molecules. In addition, virtual screening of around 18 million small drug-like compounds from ZINC database were screened at the binding pocket of the AT1 receptor via Glide/HTVS method. Filtered structures were then used in more sophisticated molecular docking simulations protocols (i.e., Glide/SP; Glide/XP; Glide/IFD; Glide/QPLD, and GOLD). However, the K⁺ ion channel/drug interactions should also be considered in studies implemented in molecular level against their cardiovascular risks. Thus, selected compounds with high docking scores via all diverse docking algorithms are also screened at the pore domain regions of human ether-a-go-go-related gene (hERG1) K⁺ channel to remove the high affinity hERG1 blocking compounds. High docking scored compounds at the AT1 with low hERG1 affinity is considered for long molecular dynamics (MD) simulations. Post-processing analysis of MD simulations assisted for better understanding of molecular mechanism of studied compounds at the binding cavity of AT1 receptor. Results of this study can be useful for designing of novel and safe AT1 inhibitors.     

Computational screening and design of S100B ligand to block S100B–p53 interaction

The binding of S100B to p53 disables the biological function of p53 as a tumor suppressor and thus causes cancer. It is very important to explore the interaction between S100B and p53 and to develop inhibitors to block the interaction in anti-cancer development. In this work, the interaction of S100B to p53 was studied using molecular dynamics (MD) at the atomic level and organic molecules have been identified as potential inhibitors to block the S100B–p53 interaction. It was indicated in the simulations that S100B residues around GLU45 and GLU46 play an important role in the binding of S100B to p53. The three dimensional structure of S100B obtained from S100B–p53 complex (PDB ID: 1DT7) was used as the target protein receptor. Multiple LUDI screenings for S100B ligands were performed using different searching radii 6.23 Å, 7.23 Å, 8.23 Å, 9.23 Å and 10.23 Å with a searching center which was defined as the geometrical center of S100B residues that are within 5 Å from the p53 C-terminal peptide in the complex. Potential organic compounds were screened from the ZINC database using LUDI program implemented in Cerius2 package and evaluated as potential S100B ligands to block the S100B–p53 interaction. The top-scored compounds were selected for binding affinity calculation. The results show that these top-scored ZINC compounds bind in the location where p53 binds and interact with S100B in a similar fashion as p53, and therefore it is expected that they have the potential to block S100B from binding to p53. The ADME and toxicity properties of the potential S100B ligands were also evaluated.     

Identification of potent virtual leads and ADME prediction of isoxazolidine podophyllotoxin derivatives as topoisomerase II and tubulin inhibitors

Towards the design of new class of podophyllotoxin to target topoisomerase II and tubulin as substantial target in cancer therapy, a series of isoxazolidine podophyllotoxin derivatives were designed. Topoisomerase in complex with etoposide and four β-tubulin in complex with zampanolide, taxol, vinblastine or colchicine were used as targets using GOLD5.2.2 as a docking module. The revealed key structural features of the highest fitness into tubulin domain have been explained as follows: (1) trans orientation of the lactone (ring D) with 5a-β, 8a-α configuration; (2) dioxolane in ring A; (3) free rotation of ring E; (4) α (R) or β (S) configuration has equal fitness in position 5; (5) 4′-OMe; (6) phosphoramide linkage; (7) ethylene bridge between the phosphate and isoxazolidine ring; (8) benzyl moiety at N²-position of isoxazolidine ring; and (9) position 5 of isoxazolidine ring accommodated with 6-bromo-9H-purine, 2-amino-6H-purin-6-one, or N-(2-oxopyrimidin-4-yl) acetamide. All of these structural features are applicable for compounds to fit properly into topoisomerase II, except (1) β (S) configuration has a higher score fitness than α (R) in position 5; (2) 4′-OH; and (3) position 5 of isoxazolidine ring accommodated better with 6-bromo-9H-purine, 2-amino-6H-purin-6-one or 7H-purin-6-amine. Computational ADMET and toxicity studies were in consensus with the docking results. Compounds holding ethylene bridge between phosphate and benzyl moiety at N²-position of isoxazolidine ring have the optimal pharmacokinetic properties and were calculated to be non-toxic. The predicted solubility profile for most of 4′-OMe containing compounds was good. This accomplished our aim in identifying promising new hits as antitumor agent with improved activity and less toxicity.     

Binding mode analysis,dynamic simulation and binding free energy calculations of the MurF ligase from Acinetobacter baumannii

MurF ligase catalyzes the final cytoplasmic step of bacterial peptidoglycan biosynthesis and, as such, is a validated target for therapeutic intervention. Herein, we performed molecular docking to identify putative inhibitors of Acinetobacter baumannii MurF (AbMurF). Based on comparative docking analysis, compound 114 (ethyl pyridine substituted 3-cyanothiophene) was predicted to potentially be the most active ligand. Computational pharmacokinetic characterization of drug-likeness of the compound showed it to fulfil all the parameters of Muegge and the MDDR rule. A molecular dynamic simulation of 114 indicated the complex to be stable on the basis of an average root mean square deviation (RMSD) value of 2.09 Å for the ligand. The stability of the complex was further supported by root mean square fluctuation (RMSF), beta factor and radius of gyration values. Analyzing the complex using radial distribution function (RDF) and a novel analytical tool termed the axial frequency distribution (AFD) illustrated that after simulation the ligand is positioned in close vicinity of the protein active site where Thr42 and Asp43 participate in hydrogen bonding and stabilization of the complex. Binding free energy calculations based on the Poisson-Boltzmann or Generalized–Born Surface Area Continuum Solvation (MM(PB/GB)SA) method indicated the van der Waals contribution to the overall binding energy of the complex to be dominant along with electrostatic contributions involving the hot spot amino acids from the protein active site. The present results indicate that the screened compound 114 may act as a parent structure for designing potent derivatives against AbMurF in specific and MurF of other bacterial pathogens in general.     

Prediction of building energy needs in early stage of design by using ANFIS

Studies performed on the prediction of building energy consumption are increasingly important for selecting the best control strategies against the excessive energy consumptions. This paper presents Adaptive Network Based Inference System (ANFIS) model to forecast building energy consumption in a cold region. The objective of this paper is to examine the feasibility and applicability of ANFIS in building energy load forecasting area. Different combinations of building samples formed by using three different form factors (FF 1/2, FF 1/1 and FF 2/1), nine azimuth angles varied 0^o–80^o, three transparency ratios of 15%, 20%, 25% and five insulation thicknesses of 0, 2.5, 5, 10 and 15 cm. Finally, it is observed that ANFIS can be a strong tool with the 96.5 and 83.8% for heating and cooling energy prediction in pre-design stage of energy efficient buildings for choosing the best combinations.     

Structure-based designing of sordarin derivative as potential fungicide with pan-fungal activity

Fungal infections have become a significant problem for immunosuppressed patients. Sordarin, a promising fungicidal agent, inhibits fungal protein synthesis by impairing elongation factor-2 (eEF2) function. Intriguingly, despite high sequence similarity among eEF2s from different species, sordarin has been shown to inhibit translation specifically in certain fungi while unable to do so in some other fungal species (e.g. Candida parapsilosis and Candida lusitaniae).The sordarin binding site on eEF2 as well as its mechanism of action is known. In a previous study, we have detailed the interactions between sordarin and eEF2 cavities from different fungal species at the molecular level and predicted the probable cause of sordarin sensitivity.Guided by our previous analysis, we aimed for computer-aided designing of sordarin derivatives as potential fungicidal agents that still remain ineffective against human eEF2. We have performed structural knowledge-based designing of several sordarin derivatives and evaluated predicted interactions of those derivatives with the sordarin-binding cavities of different eEF2s, against which sordarin shows no inhibitory action. Our analyses identify an amino-pyrrole derivative as a good template for further designing of promising broad-spectrum antifungal agents. The drug likeness and ADMET prediction on this derivative also supports its suitability as a drug candidate.