Systematic virtual screening in search of SARS CoV-2 inhibitors against spike glycoprotein: pharmacophore screening,molecular docking,ADMET analysis and MD simulations

Molecular Diversity - In the absence of efficient anti-viral medications, the coronavirus disease 2019 (COVID-19), stemming from severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), has...     

Identification of new novel scaffold for Aurora A inhibition by pharmacophore modeling and virtual screening

Aurora kinases belong to family of highly conserved serine/threonine protein kinases that are involved in diverse cell cycle events and play a major role in regulation of cell division. Abnormal expression of Aurora kinases may lead to cancer; hence, these are considered as a potential target in cancer treatment. In this research article, we identified three novel Aurora A inhibitors using modern computational tools. A four-point common 3D pharmacophore hypothesis of Aurora A (AurA) inhibitors was developed using a diverse set of 55 thienopyrimidine derivatives. A three-dimensional quantitative structure–activity relationship (3D-QSAR) study was carried out using atom-based alignment of diverse set of 55 molecules to evaluate the structure– activity relationships. Docking and 3D-QSAR studies were performed with the 3D structure of AurA to evaluate the generated pharmacophore. The pharmacophore model and 3D-QSAR results complemented the results of our docking study. The pharmacophore hypothesis, which yields the best results, was used to screen the Zinc ‘clean drug-like’ database. Various database filters such as 3D-arrangement of pharmacophoric features, predicted activity and binding interaction score were used to retrieve hits having potential AurA inhibition activity.     

The design of TOPK inhibitors using structure-based pharmacophore modeling and molecular docking based on an MD-refined homology model

Molecular Diversity - The TOPK enzyme (also known as PBK) is a serine-threonine protein kinase that is rarely detected in normal tissues yet is found to be overexpressed and activated in a variety...     

Identification of potential Mpro inhibitors for the treatment of COVID-19 by using systematic virtual screening approach

Molecular Diversity - The Corona virus Disease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the...     

Ligand-based virtual screening,molecular docking,and molecular dynamics of eugenol analogs as potential acetylcholinesterase inhibitors with biological activity against Spodoptera frugiperda

Molecular Diversity - The development of new, more selective, environmental-friendly insecticide alternatives is in high demand for the control of Spodoptera frugiperda (S. frugiperda). The major...     

Structure-based virtual screening,in silico docking,ADME properties prediction and molecular dynamics studies for the identification of potential inhibitors against SARS-CoV-2 Mpro

COVID-19 is a viral pandemic caused by SARS-CoV-2. Due to its highly contagious nature, millions of people are getting affected worldwide knocking down the delicate global socio-economic equilibrium. According to the World Health Organization, COVID-19 has affected over 186 million people with a mortality of around 4 million as of July 09, 2021. Currently, there are few therapeutic options available for COVID-19 control. The rapid mutations in SARS-CoV-2 genome and development of new virulent strains with increased infection and mortality among COVID-19 patients, there is a great need to discover more potential drugs for SARS-CoV-2 on a priority basis. One of the key viral enzymes responsible for the replication and maturation of SARS-CoV-2 is M^pro protein. In the current study, structure-based virtual screening was used to identify four potential ligands against SARS-CoV-2 M^pro from a set of 8,722 ASINEX library compounds. These four compounds were evaluated using ADME filter to check their ADME profile and druggability, and all the four compounds were found to be within the current pharmacological acceptable range. They were individually docked to SARS-CoV-2 M^pro protein to assess their molecular interactions. Further, molecular dynamics (MD) simulations was carried out on protein–ligand complex using Desmond at 100 ns to explore their binding conformational stability. Based on RMSD, RMSF and hydrogen bond interactions, it was found that the stability of protein–ligand complex was maintained throughout the entire 100 ns simulations for all the four compounds. Some of the key ligand amino acid residues participated in stabilizing the protein–ligand interactions includes GLN 189, SER 10, GLU 166, ASN 142 with PHE 66 and TRP 132 of SARS-CoV-2 M^pro. Further optimization of these compounds could lead to promising drug candidates for SARS-CoV-2 M^pro target.

     

Identifying potential inhibitors of biofilm-antagonistic proteins to promote biofilm formation: a virtual screening and molecular dynamics simulations approach

Molecular Diversity - Microbial biofilms play a critical role in environmental biotechnology and associated applications. Biofilm production can be enhanced by inhibiting the function of proteins...     

Discovery of inhibitors targeting protein tyrosine phosphatase 1B using a combined virtual screening approach

Molecular Diversity - Protein tyrosine phosphatase 1B (PTP1B) acts as a therapeutic target for type 2 diabetes. However, the major challenges of PTP1B drug discovery are the poor selectivity and...     

Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach

JAK2 and JAK3 are non-receptor protein tyrosine kinases implicated in B-cell- and T-cell-mediated diseases. Both enzymes work via different pathways but are involved in the pathogenesis of common lymphoid-derived diseases. Hence, targeting both Janus kinases together can be a potential strategy for the treatment of these diseases. In the present study, two separate pharmacophore-based 3D-QSAR models ADRR.92 ( $Q_{\mathrm{test}}^{2} 0.663, R^{2}_{\mathrm{train}} 0.849$ , F value 219.3) for JAK2 and ADDRR.142 ( $Q^{2}_{\mathrm{test}}0.655, R_{\mathrm{train}}^{2}$ 0.869, F value 206.9) for JAK3 were developed. These models were employed for the screening of a PHASE database of approximately 1.5 million compounds; subsequently, the retrieved hits were screened employing docking simulations with JAK2 and JAK3 proteins. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated to filter candidates with poor pharmacokinetic profiles. These candidates could serve as novel therapeutic agents in the treatment of lymphoid-related diseases.     

Identification of potential trypanothione reductase inhibitors among commercially available $$\upbeta $$-carboline derivatives using chemical space,lead-like and drug-like filters,pharmacophore models and molecular docking

American trypanosomiasis or Chagas disease caused by the protozoan Trypanosoma cruzi (T. cruzi) is an important endemic trypanosomiasis in Central and South America. This disease was considered to be a priority in the global plan to combat neglected tropical diseases, 2008–2015, which indicates that there is an urgent need to develop more effective drugs. The development of new chemotherapeutic agents against Chagas disease can be related to an important biochemical feature of T. cruzi: its redox defense system. This system is based on trypanothione (\(N^{1}\),\(N^{8}\)-bis(glutathyonil)spermidine) and trypanothione reductase (TR), which are rather unique to trypanosomes and completely absent in mammalian cells. In this regard, tricyclic compounds have been studied extensively due to their ability to inhibit the T. cruzi TR. However, synthetic derivatives of natural products, such as \(\upbeta \)-carboline derivatives (\(\upbeta \)-CDs), as potential TR inhibitors, has received little attention. This study presents an analysis of the structural and physicochemical properties of commercially available \(\upbeta \)-CDs in relation to compounds tested against T. cruzi in previously reported enzymatic assays and shows that \(\upbeta \)-CDs cover chemical space that has not been considered for the design of TR inhibitors. Moreover, this study presents a ligand-based approach to discover potential TR inhibitors among commercially available \(\upbeta \)-CDs, which could lead to the generation of promising \(\upbeta \)-CD candidates.     

Identification of potential inhibitors of coronavirus hemagglutinin-esterase using molecular docking,molecular dynamics simulation and binding free energy calculation

Molecular Diversity - The pandemic outbreak of the Corona viral infection has become a critical global health issue. Biophysical and structural evidence shows that spike protein possesses a high...     

基于Topomer CoMFA的吡唑啉嘧啶类IL-2诱导T细胞激酶抑制剂的3D-QSAR及分子对接

本文采用Topomer CoMFA方法对37个吡唑啉嘧啶类IL-2诱导T细胞激酶抑制剂进行三维定量构效关系研究.得到3D-QSAR模型,其交互验证系数q~2为0.728,非交叉相关系数r~2为0.994,主成分数N为8,标准估计误差SEE为0.097.结果表明该模型有较好的预测能力.采用Topomer Search技术在ZINC数据库中进行R基的筛选,并设计6个新分子.最后用分子对接技术研究了4个新分子与IL-2诱导的T细胞激酶(Itk)大分子蛋白的作用模式,从结果中可以看到,4个新分子与Itk蛋白的A/LYS391、A/MET438位点作用显著.     

Discovery and identification of PIM-1 kinase inhibitors through a hybrid screening approach

PIM-1 kinase is an important therapeutic target in the treatment of cancer. Discovery and identification of PIM-1 Inhibitors with novel scaffolds are an effective way for developing potent therapeutic agents for the treatment of cancers. Here we proposed a hybrid screening approach which combines an optimal structure-based drug design strategy and a simple pharmacophore model to discover PIM-1 kinase inhibitors. With the proposed hybrid screening approach, the SPECS database containing 204,580 molecules was screened. In total, 89 hits were obtained. Forty three of them were purchased and tested in bioassays. Finally, 5 lead compounds with novel scaffolds were identified to exhibit promising antitumor activities against human leukemia cell line MV4-11, K-562 and human prostate cancer cell line PC-3 and DU145. Their $\hbox {IC}_{50}$ values range from 4.40 to $37.96 \,\upmu \hbox {M}$ . Three hits with 3 different scaffolds were selected from these five hits for binding mode analysis. It was demonstrated that the subtle differences in the interactions of the representatives with PIM-1 kinase contribute to the different inhibitory activities. It was also demonstrated that the suggested hybrid screening approach is an effective method to discover PIM-1 inhibitors possessing different scaffolds. These leads have a strong likelihood to act as further starting points for us in the optimization and development of potent PIM-1 inhibitors.     

Identification of novel potential HIF-prolyl hydroxylase inhibitors by in silico screening

Suppression of HIF-prolyl hydroxylase (PHD) activity by small-molecule inhibitors leads to the stabilization of hypoxia inducible factor and has been recognized as promising drug target for the treatment of ischemic diseases. In this study, pharmacophore-based virtual screening and molecular docking approaches were concurrently used with suitable modifications to identify target-specific PHD inhibitors with better absorption, distribution, metabolism, and excretion properties and to readily minimize false positives and false negatives. A customized method based on the active site information of the enzyme was used to generate a pharmacophore hypothesis (AAANR). The hypothesis was validated and utilized for chemical database screening and the retrieved hit compounds were subjected to molecular docking for further refinement. AAANR hypothesis comprised three H-bond acceptor, one negative ionizable group and one aromatic ring feature. The hypothesis was validated using decoy set with a goodness of fit score of 2 and was used as a 3D query for database screening. After manual selection, molecular docking and further refinement based on the molecular interactions of inhibitors with the essential amino acid residues, 18 hits with good absorption, distribution, metabolism, and excretion (ADME) properties were selected as excellent PHD inhibitors. The best pharmacophore hypothesis, AAANR, contains chemical features required for the effective inhibition of PHD. Using AAANR, we have identified 18 potential and diverse virtual leads, which can be readily evaluated for their potency as novel inhibitors of PHD. It can be concluded that the combination of pharmacophore, molecular docking, and manual interpretation approaches can be more successful than the traditional approach alone for discovering more effective inhibitors.     

Discovery of small molecular inhibitors for interleukin-33/ST2 protein–protein interaction: a virtual screening,molecular dynamics simulations and binding free energy calculations

The interleukin-1 receptor like ST2 has emerged as a potential drug discovery target since it was identified as the receptor of the novel cytokine IL-33, which is involved in many inflammatory and autoimmune diseases. For the treatment of such IL-33-related disorders, efforts have been made to discover molecules that can inhibit the protein–protein interactions (PPIs) between IL-33 and ST2, but to date no drug has been approved. Although several anti-ST2 antibodies have entered clinical trials, the exploration of small molecular inhibitors is highly sought-after because of its advantages in terms of oral bioavailability and manufacturing cost. The aim of this study was to discover ST2 receptor inhibitors based on its PPIs with IL-33 in crystal structure (PDB ID: 4KC3) using virtual screening tools with pharmacophore modeling and molecular docking. From an enormous chemical space ZINC, a potential series of compounds has been discovered with stronger binding affinities than the control compound from a previous study. Among them, four compounds strongly interacted with the key residues of the receptor and had a binding free energy?<????20 kcal/mol. By intensive calculations using data from molecular dynamics simulations, ZINC59514725 was identified as the most potential candidate for ST2 receptor inhibitor in this study.

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Potential phytochemical inhibitors of SARS-CoV-2 helicase Nsp13: a molecular docking and dynamic simulation study

Molecular Diversity - The SARS-CoV-2 helicase Nsp13 is a promising target for developing anti-COVID drugs. In the present study, we have identified potential natural product inhibitors of...