To design a new therapeutic agent for Spleen Tyrosine Kinase (Syk), analysis of ligand-based pharmacophore modeling, 3D QSAR and molecular docking studies were performed. A consortium of 99 molecules ...with different molecular scaffolds (9.36 > pIC50>5.49) were gathered. Generated models were anatomized and essential properties required for the inhibition of Syk were assimilated. Comparative analyses of highly active, moderately active and inactive molecules helped in explaining the interactions necessary for ligand receptor binding. Further, model validation by collating the crystal structures of Syk also proved its applicability. Based on the analysis, imidazopyrazine based ligands show a strong binding affinity towards Syk active site along with good ADME properties. Going forward this study may pave a new way for designing and synthesising Syk inhibitors with better biological activities.
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•A predictive pharmacophore model of SYK selective inhibitors has been developed.•3D QSAR and Molecular docking methods are employed to assimilate probable ligand receptor interactions.•Comparative analysis of highly active, moderately active and inactive molecules to validate simulated interactions.•ADME property analysis also explored for in vivo applicability.
Prolyl endopeptidase or prolyl oligopeptidase (PEP or POP) is highly expressed in brain, and associated with autism spectrum disorders, dementia, aging and various psychological disorders, such as ...schizophrenia, mania, and neurodegeneration. To design highly potent and novel POP inhibitors, structure-based virtual screening was carried out using pharmacophore modeling and molecular docking studies. The docking based active compounds incensole (1), incensole acetate (2), incensone (3), incensfuran (4), and epi-incensole acetate (5) were selected and their dynamic behavior was studied through molecular dynamic simulation. Later, the top-ranked predicted active, (1–5) and lower-ranked predicted in-active, (6–10) compounds were tested by in-vitro assay. The in-vitro results showed that all top-ranked compounds (1–5) found significantly active against POP enzyme with IC50 values in range of 3.1 ± 0.45 to 24.4 ± 1.16 μM, while lower-ranked (6–10) were inactive, indicated accuracy of docking results. Kinetics studies on all active compounds 1–5 were carried out to investigate their mode of inhibition and dissociation constants Ki. All compounds showed competitive behaviors with Ki values in the range of 0.92–8.12 μM. The study resulted in the identification of five (1–5) diterpene based molecules from natural sources that significantly inhibit the activity of POP by competitive mode of inhibition.
Many biomedical applications, such as classification of binding specificities or bioengineering, depend on the accurate definition of protein binding interfaces. Depending on the choice of method ...used, substantially different sets of residues can be classified as belonging to the interface of a protein. A typical approach used to verify these definitions is to mutate residues and measure the impact of these changes on binding. Besides the lack of exhaustive data, this approach also suffers from the fundamental problem that a mutation introduces an unknown amount of alteration into an interface, which potentially alters the binding characteristics of the interface. In this study we explore the impact of alternative binding site definitions on the ability of a protein to recognize its cognate ligand using a pharmacophore approach, which does not affect the interface. The study also shows that methods for protein binding interface predictions should perform above approximately F-score = 0.7 accuracy level to capture the biological function of a protein.
SARS-CoV-2 infects human cells through its surface spike glycoprotein (SgP), which relies on host cell surface heparan sulfate (HS) proteoglycans that facilitate interaction with the ACE2 receptor. ...Targeting this process could lead to inhibitors of early steps in viral entry. Screening a microarray of 24 HS oligosaccharides against recombinant S1 and receptor-binding domain (RBD) proteins led to identification of only eight sequences as potent antagonists; results that were supported by detailed dual-filter computational studies. Competitive studies using the HS microarray suggested almost equivalent importance of IdoA2S–GlcNS6S and GlcNS3S structures, which were supported by affinity studies. Exhaustive virtual screening on a library of >93 000 sequences led to a novel pharmacophore with at least two 3-O-sulfated GlcN residues that can engineer unique selectivity in recognizing the RBD. This work puts forward the key structural motif in HS that should lead to potent and selective HS or HS-like agents against SARS-CoV-2.
Protein kinase 2 (CK2), an essential serine/threonine casein kinase, is considered an interesting target for cancer treatments. Different molecular modeling approaches such as pharmacophore modeling, ...molecular docking, and molecular dynamics simulations have been used to develop new CK2 inhibitors. This study presents a pharmacophore model that was generated by combining and merging the structure-based and ligand-based pharmacophore features and validated using receiver operating characteristic (ROC). Based on validation results revealing good predictive ability, this pharmacophore model was used as a three-dimensional query in a virtual screening simulation. Several compounds with different chemical scaffolds were retrieved as hits, which were further analyzed and refined using several molecular property filters. The obtained compounds were then filtered and compared to the crystallographic ligand on the basis of their predicted docking energies, binding mode, and interactions with CK2 active site residues. This step resulted in a compound with a high pharmacophore fit value and better docking energy. Molecular dynamics simulation indicated stable binding of the predicted compound to CK2 protein, characterized by root mean square deviation (RMSD) and root mean square fluctuation (RMSF) and hydrogen bond.
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One of the most frequent diseases that affect and kill men globally is prostate cancer. Treatment for prostate cancer has become unpleasant and upsetting for individuals due to the resulting ...resistance, toxicity, and adverse effects of standard chemotherapies. Consequently, we report the identification of 263 bioactive chemicals in this investigation, some of which are responsible for known anti-cancer effect from Annona muricata using molecular docking, binding free energy estimates, induced-fit docking, gene enrichment analysis, molecular dynamic simulations, and ADMET predictions as examples of in silico approaches. The top 8 scoring compounds from a screening of 263 A. muricata samples revealed varying binding affinities between −9.854 and −8.179 kcal/mol towards the Human steroid 5′-reductase 2 enzyme. Amidst the top eight scoring compounds, annopentocin A, muricatetrocin A, and annohexocin had docking scores of −9.854, −9.337, and −9.337, respectively. The compounds such as annopentocin A communicated with amino acids of medical relevance such as GLU 57, ARG 227, TYR 91, TYR 98, LEU 111, SER 31 via H-bond and TRP 53, PHE 194, 118, 223, 219, 216, LEU 20, 17, 125, 224, 111, 167, ALA 117, TYR 33, 91, 98, 107, CYS 119, ILE 112 via Hydrophobic interaction. The compounds' capacity to impede protein activity was additionally confirmed by preferable docking scores in the induced-fit docking. Annopentocin A, Muricatetrocin A, Isoannonacinone, Annomuricin A and Muricatin C obeyed Lipinski's rule of 5 with favourable toxicity as well as pharmacokinetic prediction. However, there tend to be poor solubility profile and low GI absorption by the compounds which makes them more suitable for intravenous and topical administration than oral administration for optimal efficacy.
is the bacterial strain that causes tuberculosis (TB). However, multidrug-resistant and extensively drug-resistant tuberculosis are significant obstacles to effective treatment. As a result, novel ...therapies against various strains of
have been developed. Drug development is a lengthy procedure that includes identifying target protein and isolation, preclinical testing of the drug, and various phases of a clinical trial,
, can take decades for a molecule to reach the market. Computational approaches such as QSAR, molecular docking techniques, and pharmacophore modeling have aided drug development. In this review article, we have discussed the various techniques in tuberculosis drug discovery by briefly introducing them and their importance. Also, the different databases, methods, approaches, and software used in conducting QSAR, pharmacophore modeling, and molecular docking have been discussed. The other targets targeted by these techniques in tuberculosis drug discovery have also been discussed, with important molecules discovered using these computational approaches. This review article also presents the list of drugs in a clinical trial for tuberculosis found drugs. Finally, we concluded with the challenges and future perspectives of these techniques in drug discovery.
Interleukin 17 F is a member of IL-17 cytokine family with a 50% structural homology to IL-17A and plays a significant role either alone or in combination with IL-17A towards inflammation in ...Rheumatoid arthritis (RA). A growing number of drugs targeting IL-17 pathway are being tested against population specific disease markers. The major objective of this research was to investigate the anti-inflammatory effect of Anakinra (an IL-1 R1 inhibitor) and Ustekinumab (an IL-12 and IL-23 inhibitor) by targeting IL17F. The three dimensional structures of IL17F was taken from PDB while structures of drugs were taken from PubChem database. Docking was performed using MOE and Schrodinger ligand docking software and binding energies, including s-score using London-dG fitness function and glide score using glide internal energy function, between drug and targets were compared. Furthermore, Protein-Drug complex were subjected to 150 ns Molecular Dynamics (MD) Simulations using Schrodinger's Desmond Module. Docking and MD simulation results suggest anakinra as a more potent IL17F inhibitor and forming a more structurally stable complex.
Communicated by Ramaswamy H. Sarma
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