Identification of Potential Anti-Tubercular Inhibitors through Virtual Screening, DFT, and Molecular Dynamics Simulation Studies

DNA gyrase brings negative supercoils into DNA and loosens up certain positive supercoils that collect during replication and transcription and is a notable antibacterial target. To fight against the menace of antibiotic-resistant bacterial infections, we have employed various computational tools like high throughput virtual screening (HTVS), standard precision (SP) docking, extra precision (XP) docking, and molecular dynamics (MD) simulation studies to identify some potential DNA gyrase inhibitors. A focused library of 5968 anti-bacterial compounds was screened using the HTVS docking protocol of the glide module of Maestro. The top 200 docked compounds were further filtered using SP and XP docking protocols, and their free binding energies were calculated using MM-GBSA studies. The binding and stability of the top two compounds which showed better docking scores than the co-crystallized ligand (Clorobiocin) of DNA gyrase (PDB ID: 1KZN) were further probed by MD simulation of 100 ns using GROMACS. MD simulation study suggested that the compounds AM1 and AM5 form a stable complex with DNA gyrase with a good number of hydrogen bonds. XP docking study showed that interaction with the crucial amino acids for compounds AM1 and AM5 was like the co-crystallized ligand. These compounds were also predicted to be drug-like molecules with good water solubility and excellent absorption profiles. Based on the above studies, herein we report compounds AM1 (1R,3S)-1-(2-((3-(ammoniomethyl)phenyl)amino)-2-oxoethyl)-3-carbamoylpiperidin-1-ium and AM5 (1'S,2 s,4R)-4-ammonio-6-ethyl-1'-methylspiro[chromane-2,4'-piperidin]-1'-ium as potential DNA gyrase inhibitors which can be further developed as a potential lead against the menace of antibiotic resistance.

Recent outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a pandemic of COVID-19. The absence of a therapeutic drug and vaccine is causing severe loss of life and economy worldwide. SARS-CoV and SARS-CoV-2 employ the host cellular serine protease TMPRSS2 for spike (S) protein priming for viral entry into host cells. A potential way to reduce the initial site of SARS-CoV-2 infection may be to inhibit the activity of TMPRSS2. In the current study, the three-dimensional structure of TMPRSS2 was generated by homology modelling and subsequently validated with a number of parameters. The structure-based virtual screening of Selleckchem database was performed through ‘Virtual Work Flow’ (VSW) to find out potential lead-like TMPRSS2 inhibitors. Camostat and bromhexine are known TMPRSS2 inhibitor drugs, hence these were used as control molecules throughout the study. Based on better dock score, binding-free energy and binding interactions compared to the control molecules, six molecules (Neohesperidin, Myricitrin, Quercitrin, Naringin, Icariin, and Ambroxol) were found to be promising against the TMPRSS2. Binding interactions analysis revealed a number of significant binding interactions with binding site amino residues of TMPRSS2. The all-atoms molecular dynamics (MD) simulation study indicated that all proposed molecules retain inside the receptor in dynamic states. The binding energy calculated from the MD simulation trajectories also favour the strong affinity of the molecules towards the TMPRSS2. Proposed molecules belong to the bioflavonoid class of phytochemicals and are reported to possess antiviral activity, our study indicates their possible potential for application in COVID-19.

Identification of novel serotonin reuptake inhibitors targeting central and allosteric binding sites: A virtual screening and molecular dynamics simulations study

A computational journey in anticancer drug discovery: Exploring AKT1 inhibition by novel oxadiazoles using molecular docking, ADMET, density functional theory and molecular dynamic simulation.

Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies

Diabetic wounds (DWs) are the major end-stage manifestation encountered in diabetic patients. The two major pathways involved in the pathogenesis of DW are impaired angiogenesis and unnecessary NETosis, which are regulated by a common enzyme called protein kinase C (PKC)-βII. PKC-βII is a conventional isoform of PKC family that can be activated by calcium and diacylglycerol. PKC-βII possesses a specific expression profile and plays a distinct role in various cellular and molecular functions. The pathogenic role of PKC-βII and its involvement in the impairment of wound healing suggested that PKC-βII plays a potential role in DW progression. Hence, there is a renewed interest in developing specific inhibitors of PKC-βII. In the present study, receptor-based virtual screening was performed for the identification of potential PKC-βII inhibitors using TimTec, Enamine, Zinc and Specs databases. A total of 595 candidate compounds were evaluated based on absorption, distribution, metabolism, excretion and toxicity, standard precision docking. Further, extra-precision docking and binding free energy calculations were carried out for top-ranked compounds. Based on Glide score and protein-ligand interactions, we have identified compound 1 as a potential inhibitor. Finally, molecular dynamics (MD) simulation was performed for top compound 1 using the Desmond module (Schrödinger suite) to identify the structural stability of the protein-ligand complex. Gratifyingly, MD trajectory analysis demonstrated the stable binding conformation of compound 1 with PKC-βII enzyme. In silico approaches incorporated in this study provide a set of new putative PKC-βII inhibitors which could be potential leads to develop DW therapeutics.

The bacterium Bacillus coagulans has attracted interest because of its ability to produce spores and advantageous probiotic traits, such as facilitating food digestion in the intestine, managing some disorders, and controlling the symbiotic microbiota. Spore-forming probiotic bacteria are especially important in the probiotic industry compared to non-spore-forming bacteria due to their stability during production and high resistance to adverse factors such as stomach acid. When spore-forming bacteria are exposed to environmental stresses, they enter the sporulation pathway to survive. This pathway is activated by the final phosphorylation of the master regulator of spore response, Spo0A, and upon achieving the phosphorylation threshold. Spo0A is indirectly inhibited by some enzymes of the aspartate response regulator phosphatase (Rap) family, such as RapJ. RapJ is one of the most important Rap enzymes in the sporogenesis pathway, which is naturally inhibited by the pentapeptides. This study used structure-based virtual screening and molecular dynamics (MD) simulation studies to find potential RapJ hits that could induce the sporulation pathway. The crystal structures of RapJ complexed with pentapeptide clearly elucidated their interactions with the enzyme active site. Based on the binding compartment, through molecular docking, MD simulation, hydrogen bonds, and binding-free energy calculations, a series of novel hits against RapJ named tandutinib, infigratinib, sitravatinib, linifanib, epertinib, surufatinib, and acarbose were identified. Among these compounds, acarbose obtained the highest score, especially in terms of the number of hydrogen bonds, which plays a major role in stabilizing RapJ-ligand complexes, and also according to the occupancy percentages of hydrogen bonds, its hydrogen bonds were more stable during the simulation time. Consequently, acarbose is probably the most suitable hit for RapJ enzyme. Notably, experimental validation is crucial to confirm the effectiveness of the selected ligands.

In this study, a comprehensive investigation of a set of phytochemicals to identify potential inhibitors for the Forkhead box protein M1 (FOXM1) was conducted. FOXM1 is overexpressed in glioblastoma (GBM) cells and plays a crucial role in cell cycle progression, proliferation, and invasion. FOXM1 inhibitors have shown promising results in preclinical studies, and ongoing clinical trials are assessing their efficacy in GBM patients. However, there are limited studies on the identification of novel compounds against this attractive therapeutic target. To address this, the NPACT database containing 1,574 phytochemicals was used, employing a hierarchical multistep docking approach, followed by an estimation of relative binding free energy. By fixing user-defined XP-dock and MM-GBSA cut-off scores of −6.096 and −37.881 kcal/mol, the chemical space was further narrowed. Through exhaustive analysis of molecular binding interactions and various pharmacokinetics profiles, we identified four compounds, namely NPACT00002, NPACT01454, NPACT00856, and NPACT01417, as potential FOXM1 inhibitors. To assess the stability of protein-ligand binding in dynamic conditions, 100 ns Molecular dynamics (MD) simulations studies were performed. Furthermore, Molecular mechanics with generalized Born and surface area solvation (MM-GBSA) based binding free energy estimations of the entire simulation trajectories revealed a strong binding affinity of all identified compounds towards FOXM1, surpassing that of the control drug Troglitazone. Based on extensively studied multistep docking approaches, we propose that these molecules hold promise as FOXM1 inhibitors for potential therapeutic applications in GBM. However, experimental validation will be necessary to confirm their efficacy as targeted therapies.

Alzheimer is a severe memory and cognitive impairment neurodegenerative disease that is the most common cause of dementia worldwide and characterized by the pathological accumulation of tau protein and amyloid-beta peptides. In this study, we have developed E-pharmacophore modeling to screen the eMolecules database with the help of a reported co-crystal structure bound with Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1). Flumemetamol, florbetaben, and florbetapir are currently approved drugs for use in the clinical diagnosis of Alzheimer’s disease. Despite the benefits of commercially approved drugs, there is still a need for novel diagnostic agents with enhanced physicochemical and pharmacokinetic properties compared to those currently used in clinical practice and research. In the E-pharmacophore modeling results, it is revealed that two aromatic rings (R19, R20), one donor (D12), and one acceptor (A8) are obtained, and also that similar pharmacophoric features of compounds are identified from pharmacophore-based virtual screening. The identified screened hits were filtered for further analyses using structure-based virtual screening and MM/GBSA. From the analyses, top hits such as ZINC39592220 and en1003sfl.46293 are selected based on their top docking scores (−8.182 and −7.184 Kcal/mol, respectively) and binding free energy (−58.803 and −56.951 Kcal/mol, respectively). Furthermore, a molecular dynamics simulation and MMPBSA study were performed, which revealed admirable stability and good binding free energy throughout the simulation period. Moreover, Qikprop results revealed that the selected, screened hits have good drug-likeness and pharmacokinetic properties. The screened hits ZINC39592220 and en1003sfl.46293 could be used to develop drug molecules against Alzheimer’s disease.

AimsCoronavirus disease 2019 (COVID-19) has appeared in Wuhan, China but the fast transmission has led to its widespread prevalence in various countries, which has made it a global concern. Another concern is the lack of definitive treatment for this disease. The researchers tried different treatment options which are not specific. The current study aims to identify potential small molecule inhibitors against the main protease protein of SARS-CoV-2 by the computational approach. Main methodsIn this study, a virtual screening procedure employing docking of the two different datasets from the ZINC database, including 1615 FDA approved drugs and 4266 world approved drugs were used to identify new potential small molecule inhibitors for the newly released crystal structure of main protease protein of SARS-CoV-2. In the following to validate the docking result, molecular dynamics simulations were applied on selected ligands to identify the behavior and stability of them in the binding pocket of the main protease in 150 nanoseconds (ns). Furthermore, binding energy using the MMPBSA approach was also calculated. Key findingsThe result indicates that simeprevir (Hepatitis C virus NS3/4A protease inhibitor) and pyronaridine (antimalarial agent) could fit well to the binding pocket of the main protease and because of some other beneficial features including broad-spectrum antiviral properties and ADME profile, they might be a promising drug candidate for repurposing to the treatment of COVID-19. SignificanceSimeprevir and pyronaridine were selected by the combination of virtual screening and molecular dynamics simulation approaches as a potential candidate for treatment of COVID-19.

The discovery of a safe and efficacious drug is a complex, time-consuming, and expensive process. Computational methodologies driven by cheminformatics tools play a central role in the high-throughput lead discovery and optimization process especially when the structure of the biological target is known. Monoamine oxidases are the membrane-bound FAD-containing enzymes and the isoform monoamine oxidase-B (MAO-B) is an attractive target for treating diseases like Alzheimer’s disease, Parkinson’s disease, glioma, etc. In the current study, we have used a pharmacophore-based virtual screening technique for the identification of new small molecule MAO-B inhibitors. Safinamide was used for building a pharmacophore model and the developed model was used to probe the ZINC database for potential hits. The obtained hits were filtered against drug-likeness and PAINS. Out of the hit’s library, two compounds ZINC02181408, ZINC08853942 (most active), and ZINC53327382 (least active) were further subjected to molecular docking and dynamics simulation studies to assess their virtual binding affinities and stability of the resultant protein–ligand complex. The docking studies revealed that active ligands were well accommodated within the active site of MAO-B and interacted with both substrate and entrance cavity residues. MD simulation studies unveiled additional hydrogen bond interactions with the substrate cavity residues, Tyr398 and Tyr435 that are crucial for the catalytic role of MAO-B. Moreover, the predicted ADMET parameters suggest that the compounds ZINC08853942 and ZINC02181408 are suitable for CNS penetration. Thus, the attempted computational campaign yielded two potential MAO-B inhibitors that merit further experimental investigation. Communicated by Ramaswamy H. Sarma

Sphingosine kinases (SphKs) as lipid kinases catalyze the phosphorylation of sphingosine (Sph) to sphingosine-1-phosphate (S1P). Targeting the S1P signaling pathway is a significant strategy for many human diseases. Herein, we evaluated main prenylated bioactive components of a medicinal plant and performed a virtual screening study with flavonoid compounds and then, molecular docking and molecular dynamics (MD) simulation for the targeted cancer therapy. In silico ADMET and drug-likeness results were determined by BIOVIA Discovery Studio (DS). Molecular docking and molecular dynamics (MD) simulations were carried out by using Glide/SP and Desmond of Maestro with the filtered ligands. Glide/SP docking results showed higher binding affinity with xanthohumol (XN), 8-prenylnaringenin (8-PN), and neobavaisoflavone against SphK1. Three hits displayed strong hydrogen binding between the specific amino acid residues of targeting SphK1. There were no significant structural changes between SphK1-XN and SphK1-neobavaisoflavone complexes during 200 ns MD simulation analysis performed by GROMACS. Root-mean square deviation (RMSD) average values of XN- and neobavaisoflavone-protein complexes were compared to free SphK1 and were found as 0.2626 nm, 0.2589 nm, and 0.2508 nm, respectively. As a result, XN and 8-PN, and neobavaisoflavone have been determined as potential inhibitor candidates of SphK1 to examine for further in vitro and in vivo studies.

Pharmacoinformatics exploration of polyphenol oxidases leading to novel inhibitors by virtual screening and molecular dynamic simulation study

Sphingosine kinase 1 (SphK1) dysfunction is well-known to be linked to various severe diseases, including breast, lung, prostate, and hematological cancers. Due to its crucial function in the onset of cancer and its progression, it is considered a notable drug target for anticancer therapy. Small molecule inhibitors with high specificity and efficacy towards SphK1 are needed for their therapeutic use. In order to find possible SphK1 inhibitors, we conducted a stepwise structure-based virtual screening of plant-based molecules available from the IMPPAT library. A multi-step virtual screening, including physicochemical and ADMET evaluation, PAINS, molecular docking, PASS analysis followed by molecular dynamics (MD) simulation and principal component analysis, identifies two compounds, Gummadiol and Isoarboreol, against SphK1. All-atom MD simulations were performed for 100 ns which examined the structural changes and stability of the docked complexes in the aqueous environment. The time evolution data of structural deviations and compactness, PCA and free energy landscapes suggested that the binding of Gummadiol and Isoarboreol with SphK1 is considerably stable throughout the trajectory. The study highlighted the use of phytochemicals in anticancer therapeutics and presented Gummadiol and Isoarboreol as promising inhibitors of SphK1. Communicated by Ramaswamy H. Sarma

In this study, we searched for potential DNA GyrB inhibitors using pharmacophore-based virtual screening followed by molecular docking and molecular dynamics simulation approaches. For this purpose, a set of 248 DNA GyrB inhibitors was collected from the literature and a well-validated pharmacophore model was generated. The best pharmacophore model explained that two each of hydrogen bond acceptors and hydrophobicity regions were critical for inhibition of DNA GyrB. Good statistical results of the pharmacophore model indicated that the model was robust in nature. Virtual screening of molecular databases revealed three molecules as potential antimycobacterial agents. The final screened promising compounds were evaluated in molecular docking and molecular dynamics simulation studies. In the molecular dynamics studies, RMSD and RMSF values undoubtedly explained that the screened compounds formed stable complexes with DNA GyrB. Therefore, it can be concluded that the compounds identified may have potential for the treatment of TB.