Discovery of Novel Acetylcholinesterase Inhibitors as Potential Candidates for the Treatment of Alzheimer's Disease.

Acetylcholinesterase (AChE) catalyzes the hydrolysis of neurotransmitter acetylcholine to acetate and choline in a synaptic cleft. Deficits in cholinergic neurotransmitters are linked closely with the progression of Alzheimer's disease (AD), which is a neurodegenerative disorder characterized by memory impairment, and a disordered cognitive function. Since the previously approved AChE inhibitors, donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon), have side effects and several studies are being carried out out to develop novel AD drugs, we have applied a three-dimensional quantitative structure-activity relationship (3D QSAR) and structure-based pharmacophore modeling methodologies to identify potential candidate inhibitors against AChE. Herein, 3D QSAR and structure-based pharmacophore models were built from known inhibitors and crystal structures of human AChE in complex with donepezil, galantamine, huperzine A, and huprine W, respectively. The generated models were used as 3D queries to screen new scaffolds from various chemical databases. The hit compounds obtained from the virtual screening were subjected to an assessment of drug-like properties, followed by molecular docking. The final hit compounds were selected based on binding modes and molecular interactions in the active site of the enzyme. Furthermore, molecular dynamics simulations for AChE in complex with the final hits were performed to evaluate that they maintained stable interactions with the active site residues. The binding free energies of the final hits were also calculated using molecular mechanics/Poisson-Boltzmann surface area method. Taken together, we proposed that these hits can be promising candidates for anti-AD drugs.

Discovery of Non-Peptidic Compounds against Chagas Disease Applying Pharmacophore Guided Molecular Modelling Approaches.

Chagas disease is one of the primary causes of heart diseases accounting to 50,000 lives annually and is listed as the neglected tropical disease. Because the currently available therapies have greater toxic effects with higher resistance, there is a dire need to develop new drugs to combat the disease. In this pursuit, the 3D QSAR ligand-pharmacophore (pharm 1) and receptor-based pharmacophore (pharm 2) search was initiated to retrieve the candidate compounds from universal natural compounds database. The validated models were allowed to map the universal natural compounds database. The obtained lead candidates were subjected to molecular docking against cysteine protease (PDB code: 1ME3) employing -Cdocker available on the discovery studio. Subsequently, two Hits have satisfied the selection criteria and were escalated to molecular dynamics simulation and binding free energy calculations. These Hits have demonstrated higher dock scores, displayed interactions with the key residues portraying an ideal binding mode complemented by mapping to all the features of pharm 1 and pharm 2. Additionally, they have rendered stable root mean square deviation (RMSD) and potential energy profiles illuminating their potentiality as the prospective antichagastic agents. The study further demonstrates the mechanism of inhibition by tetrad residues compromising of Gly23 and Asn70 holding the ligand at each ends and the residues Gly65 and Gly160 clamping the Hits at the center. The notable feature is that the Hits lie in close proximity with the residues Glu66 and Leu67, accommodating within the S1, S2 and S3 subsites. Considering these findings, the study suggests that the Hits may be regarded as effective therapeutics against Chagas disease.

Competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors, prenylated caged xanthones from Garcinia hanburyi and their inhibitory mechanism.

Protein tyrosine phosphatase 1B (PTP1B) plays important role in diabetes, obesity and cancer. The methanol extract of the gum resin of Garcinia hanburyi (G. hanburyi) showed potent PTP1B inhibition at 10µg/ml. The active compounds were identified as prenylated caged xanthones (1-9) which inhibited PTP1B in dose-dependent manner. Carboxybutenyl group within caged motif (A ring) was found to play a critical role in enzyme inhibition such as 1-6 (IC50s=0.47-4.69µM), whereas compounds having hydroxymethylbutenyl 7 (IC50=70.25µM) and methylbutenyl 8 (IC50>200µM) showed less activity. The most potent inhibitor, gambogic acid 1 (IC50=0.47µM) showed 30-fold more potency than ursolic acid (IC50=15.5µM), a positive control. In kinetic study, all isolated xanthones behaved as competitive inhibitors which were fully demonstrated with Km, Vmax and Kik/Kiv ratio. It was also proved that inhibitor 1 operated under the enzyme isomerization model having k5=0.0751µM-1S-1, k6=0.0249µM-1S-1 and Kiapp=0.499µM. To develop a pharmacophore model, we explored the binding sites of compound 1 and 7 in PTP1B. These modeling results were in agreement with our findings, which revealed that the inhibitory activities are tightly related to caged motif and prenyl group in A ring.

MP-V1 from the Venom of Social Wasp Vespula vulgaris Is a de Novo Type of Mastoparan that Displays Superior Antimicrobial Activities.

Mastoparans from the venom of social wasps have attracted considerable attention as effective antibiotic candidates. In this study, mastoparan V1 (MP-V1) from Vespula vulgaris was first disclosed to have a peptide amino acid sequence distinct from typical mastoparans and its biochemical properties and antimicrobial effects were compared with those of typical mastoparans MP-L, -X(V) and -B. Circular dichroism (CD) spectroscopy revealed that MP-V1 and -X(V) form more stable α-helical conformations in lipid membrane-like environments than MP-L and -B. In parallel, these two also showed more effective antimicrobial activities against the pathogens than did MP-L and -B. Although MP-V1 had a less stable α-helical conformation than MP-X(V), it showed stronger antimicrobial effects against Streptococcus mutans and Salmonella enterica than MP-X(V). In the meantime, analysis of hemolytic activity revealed a range of doses (~50 µM) that exhibited little potent cytotoxicity on human erythrocytes. Finally, the atypical MP-V1 peptide amino acid sequence provided important clues to understanding its antimicrobial mechanism from a structural perspective. Therefore, it has been concluded that MP-V1 is a de novo type of mastoparan with superior antimicrobial activities against both pathogenic bacteria and fungi, which may be useful in developing multipurpose antimicrobial drugs against infectious diseases.

Structural importance of the C-terminal region in pig aldo-keto reductase family 1 member C1 and their effects on enzymatic activity.

BACKGROUND: Pig aldo-keto reductase family 1 member C1 (AKR1C1) belongs to AKR superfamily which catalyzes the NAD(P)H-dependent reduction of various substrates including steroid hormones. Previously we have reported two paralogous pig AKR1C1s, wild-type AKR1C1 (C-type) and C-terminal-truncated AKR1C1 (T-type). Also, the C-terminal region significantly contributes to the NADPH-dependent reductase activity for 5α-DHT reduction. Molecular modeling studies combined with kinetic experiments were performed to investigate structural and enzymatic differences between wild-type AKR1C1 C-type and T-type. RESULTS: The results of the enzyme kinetics revealed that Vmax and kcat values of the T-type were 2.9 and 1.6 folds higher than those of the C-type. Moreover, catalytic efficiency was also 1.9 fold higher in T-type compared to C-type. Since x-ray crystal structures of pig AKR1C1 were not available, three dimensional structures of the both types of the protein were predicted using homology modeling methodology and they were used for molecular dynamics simulations. The structural comparisons between C-type and T-type showed that 5α-DHT formed strong hydrogen bonds with catalytic residues such as Tyr55 and His117 in T-type. In particular, C3 ketone group of the substrate was close to Tyr55 and NADPH in T-type. CONCLUSIONS: Our results showed that 5α-DHT binding in T-type was more favorable for catalytic reaction to facilitate hydride transfer from the cofactor, and were consistent with experimental results. We believe that our study provides valuable information to understand important role of C-terminal region that affects enzymatic properties for 5α-DHT, and further molecular mechanism for the enzyme kinetics of AKR1C1 proteins.

Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling.

AIM: Recent evidence suggests that aldo-keto reductase family 1 B10 (AKR1B10) may be a potential diagnostic or prognostic marker of human tumors, and that AKR1B10 inhibitors offer a promising choice for treatment of many types of human cancers. The aim of this study was to identify novel chemical scaffolds of AKR1B10 inhibitors using in silico approaches. METHODS: The 3D QSAR pharmacophore models were generated using HypoGen. A validated pharmacophore model was selected for virtual screening of 4 chemical databases. The best mapped compounds were assessed for their drug-like properties. The binding orientations of the resulting compounds were predicted by molecular docking. Density functional theory calculations were carried out using B3LYP. The stability of the protein-ligand complexes and the final binding modes of the hit compounds were analyzed using 10 ns molecular dynamics (MD) simulations. RESULTS: The best pharmacophore model (Hypo 1) showed the highest correlation coefficient (0.979), lowest total cost (102.89) and least RMSD value (0.59). Hypo 1 consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one ring aromatic and one hydrophobic feature. This model was validated by Fischer's randomization and 40 test set compounds. Virtual screening of chemical databases and the docking studies resulted in 30 representative compounds. Frontier orbital analysis confirmed that only 3 compounds had sufficiently low energy band gaps. MD simulations revealed the binding modes of the 3 hit compounds: all of them showed a large number of hydrogen bonds and hydrophobic interactions with the active site and specificity pocket residues of AKR1B10. CONCLUSION: Three compounds with new structural scaffolds have been identified, which have stronger binding affinities for AKR1B10 than known inhibitors.

New insights in the activation of human cholesterol esterase to design potent anti-cholesterol drugs.

Primary hypercholesterolemia is the root cause for major health issues like coronary heart disease and atherosclerosis. Regulating plasma cholesterol level, which is the product of biosynthesis as well as dietary intake, has become one of the major therapeutic strategies to effectively control these diseases. Human cholesterol esterase (hCEase) is an interesting target involved in the regulation of plasma cholesterol level and thus inhibition of this enzyme is highly effective in the treatment of hypercholesterolemia. This study was designed to understand the activation mechanism that enables the enzyme to accommodate long chain fatty acids and to identify the structural elements for the successful catalysis. Primarily the activation efficiencies of three different bile salts were studied and compared using molecular dynamics simulations. Based on the conformations of major surface loops, hydrogen bond interactions, and distance analyses, taurocholate was concluded as the preferred activator of the enzyme. Furthermore, the importance of two bile salt binding sites (proximal and remote) and the crucial role of 7α-OH group of the bile salts in the activation of hCEase was examined and evidenced. The results of our study explain the structural insights of the activation mechanism and show the key features of the bile salts responsible for the enzyme activation which are very useful in hypolipidemic drug designing strategies.

Discovery of Lonafarnib-Like Compounds: Pharmacophore Modeling and Molecular Dynamics Studies.

Progeria is a globally noticed rare genetic disorder manifested by premature aging with no effective treatment. Under these circumstances, farnesyltransferase inhibitors (FTIs) are marked as promising drug candidates. Correspondingly, a pharmacophore model was generated exploiting the features of lonafarnib. The selected pharmacophore model was allowed to screen the InterBioScreen natural compound database to retrieve the potential lead candidates. A series of filtering steps were applied to assess the drug-likeness of the compounds. The obtained compounds were advanced to molecular docking employing the CDOCKER module available with Discovery Studio (DS). Subsequently, three compounds (Hits) have displayed a higher dock score and demonstrated key residue interactions with stable molecular dynamics simulation results compared to the reference compound. Taken together, we therefore put forth three identified Hits as FTIs that may further serve as chemical spaces in designing new compounds.

A Computational Approach with Biological Evaluation: Combinatorial Treatment of Curcumin and Exemestane Synergistically Regulates DDX3 Expression in Cancer Cell Lines.

DDX3 belongs to RNA helicase family that demonstrates oncogenic properties and has gained wider attention due to its role in cancer progression, proliferation and transformation. Mounting reports have evidenced the role of DDX3 in cancers making it a promising target to abrogate DDX3 triggered cancers. Dual pharmacophore models were generated and were subsequently validated. They were used as 3D queries to screen the InterBioScreen database, resulting in the selection of curcumin that was escalated to molecular dynamics simulation studies. In vitro anti-cancer analysis was conducted on three cell lines such as MCF-7, MDA-MB-231 and HeLa, which were evaluated along with exemestane. Curcumin was docked into the active site of the protein target (PDB code 2I4I) to estimate the binding affinity. The compound has interacted with two key residues and has displayed stable molecular dynamics simulation results. In vitro analysis has demonstrated that both the candidate compounds have reduced the expression of DDX3 in three cell lines. However, upon combinatorial treatment of curcumin (10 and 20 µM) and exemestane (50 µM) a synergism was exhibited, strikingly downregulating the DDX3 expression and has enhanced apoptosis in three cell lines. The obtained results illuminate the use of curcumin as an alternative DDX3 inhibitor and can serve as a chemical scaffold to design new small molecules.

Structure-Based Drug Designing Recommends HDAC6 Inhibitors To Attenuate Microtubule-Associated Tau-Pathogenesis.

Protein acetylation and deacetylation play vital roles in the structural and physiological behavior of target proteins. Histone deacetylase 6 (HDAC6) remains a key therapeutic target in several chronic diseases such as cancer, neurodegenerative, and hematological diseases. In tau-pathogenesis, HDAC6 tightly regulates microtubule-associated tau physiology, and its inhibition suppresses Alzheimer's phenotype. To this end, the current study has identified novel HDAC6 inhibitors by structure-based drug designing method. A pharmacophore was generated from HDAC6 in complex with trichostatin A. The selected pharmacophore had five features including two hydrogen bond donors, one hydrogen bond acceptor, and two hydrophobic features. Pharmacophore validation obtained the highest GH score of 0.80. By applying Lipinski's rule of five and ADMET Descriptors, a drug-like database of 29 183 molecules was generated from the Zinc Natural Product Database. The validated pharmacophore screened 841 drug-like molecules and was subsequently subjected to molecular docking in the active site of HDAC6. Molecular docking identified 11 hits, where they showed the highest ChemPLP score (>90.00), stable conformation, and hydrogen-bond interactions with catalytic residues of HDAC6. Finally, molecular dynamics simulation identified three molecules as potent HDAC6 inhibitors with stable root-mean-square deviation and the highest number of hydrogen bonds with the catalytic residues of HDAC6. Overall, we recommend three novel inhibitors of HDAC6, capable of suppressing the microtubule-associated tau-pathogenesis.

Natural compounds as potential Hsp90 inhibitors for breast cancer-Pharmacophore guided molecular modelling studies.

Breast cancer is one of the major impediments affecting women globally. The ATP-dependant heat shock protein 90 (Hsp90) forms the central component of molecular chaperone machinery that predominantly governs the folding of newly synthesized peptides and their conformational maturation. It regulates the stability and function of numerous client proteins that are frequently upregulated and/or mutated in cancer cells, therefore, making Hsp90 inhibition a promising therapeutic strategy for the development of new efficacious drugs to treat breast cancer. In the present in silico investigation, a structure-based pharmacophore model was generated with hydrogen bond donor, hydrogen bond acceptor and hydrophobic features complementary to crucial residues Ala55, Lys58, Asp93, Ile96, Met98 and Thr184 directed at inhibiting the ATP-binding activity of Hsp90. Subsequently, the phytochemical dataset of 3210 natural compounds was screened to retrieve the prospective inhibitors after rigorous validation of the model pharmacophore. The retrieved 135 phytocompounds were further filtered by drug-likeness parameters including Lipinski's rule of five and ADMET properties, then investigated via molecular docking-based scoring. Molecular interactions were assessed using Genetic Optimisation for Ligand Docking program for 95 drug-like natural compounds against Hsp90 along with two clinical drugs as reference compounds - Geldanamycin and Radicicol. Docking studies revealed three phytochemicals are better than the investigated clinical drugs. The reference and hit compounds with dock scores of 48.27 (Geldanamycin), 40.90 (Radicicol), 73.04 (Hit1), 72.92 (Hit2) and 68.12 (Hit3) were further validated for their binding stability through molecular dynamics simulations. We propose that the non-macrocyclic scaffolds of three identified phytochemicals might aid in the development of novel therapeutic candidates against Hsp90-driven cancers.

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders.

Deregulation of Cdk5 is a hallmark in neurodegenerative diseases and its complex with p25 forms Cdk5/p25, thereby causes severe neuropathological insults. Cdk5/p25 abnormally phosphorylates tau protein, and induces tau-associated neurofibrillary tangles in neurological disorders. Therefore, the pharmacological inhibition of Cdk5/p25 alleviates tau-associated neurological disorders. Herein, computational simulations probed two candidate inhibitors of Cdk5/p25. Structure-based pharmacophore investigated the essential complementary chemical features of ATP-binding site of Cdk5 in complex with roscovitine. Resultant pharmacophore harbored polar interactions with Cys83 and Asp86 residues and non-polar interactions with Ile10, Phe80, and Lys133 residues of Cdk5. The chemical space of selected pharmacophore was comprised of two hydrogen bond donors, one hydrogen bond acceptor, and three hydrophobic features. Decoy test validation of pharmacophore obtained highest Guner-Henry score (0.88) and enrichment factor score (7.23). The screening of natural product drug-like databases by validated pharmacophore retrieved 1126 compounds as candidate inhibitors of Cdk5/p25. The docking of candidate inhibitors filtered 10 molecules with docking score >80.00 and established polar and non-polar interactions with the ATP-binding site residues of Cdk5/p25. Finally, molecular dynamics simulation and binding free energy analyses identified two candidate inhibitors of Cdk5/p25. During 30 ns simulation, the candidate inhibitors established <3.0 Šroot mean square deviation and stable hydrogen bond interactions with the ATP-binding site residues of Cdk5/p25. The final candidate inhibitors obtained lowest binding free energies of -122.18 kJ/mol and - 117.26 kJ/mol with Cdk5/p25. Overall, we recommend two natural product candidate inhibitors to target the pharmacological inhibition of Cdk5/p25 in tau-associated neurological disorders.

In Silico Study Probes Potential Inhibitors of Human Dihydrofolate Reductase for Cancer Therapeutics.

Dihydrofolate reductase (DHFR) is an essential cellular enzyme and thereby catalyzes thereduction of dihydrofolate to tetrahydrofolate (THF). In cancer medication, inhibition of humanDHFR (hDHFR) remains a promising strategy, as it depletes THF and slows DNA synthesis and cellproliferation. In the current study, ligand-based pharmacophore modeling identified and evaluatedthe critical chemical features of hDHFR inhibitors. A pharmacophore model (Hypo1) was generatedfrom known inhibitors of DHFR with a correlation coefficient (0.94), root mean square (RMS)deviation (0.99), and total cost value (125.28). Hypo1 was comprised of four chemical features,including two hydrogen bond donors (HDB), one hydrogen bond acceptor (HBA), and onehydrophobic (HYP). Hypo1 was validated using Fischer's randomization, test set, and decoy setvalidations, employed as a 3D query in a virtual screening at Maybridge, Chembridge, Asinex,National Cancer Institute (NCI), and Zinc databases. Hypo1-retrieved compounds were filtered byan absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment test andLipinski's rule of five, where the drug-like hit compounds were identified. The hit compounds weredocked in the active site of hDHFR and compounds with Goldfitness score was greater than 44.67(docking score for the reference compound), clustering analysis, and hydrogen bond interactionswere identified. Furthermore, molecular dynamics (MD) simulation identified three compounds asthe best inhibitors of hDHFR with the lowest root mean square deviation (1.2 Å to 1.8 Å), hydrogenbond interactions with hDHFR, and low binding free energy (-127 kJ/mol to -178 kJ/mol). Finally,the toxicity prediction by computer (TOPKAT) affirmed the safety of the novel inhibitors of hDHFRin human body. Overall, we recommend novel hit compounds of hDHFR for cancer and rheumatoidarthritis chemotherapeutics.

Investigation of novel chemical scaffolds targeting prolyl oligopeptidase for neurological therapeutics.

Prolyl oligopeptidase (POP) is a potential therapeutic target for treatment of several neurological disorders and α-synucleinopathies including Parkinson's disease. Most of the known POP inhibitors failed in the clinical trials due to poor pharmacokinetic properties and blood-brain impermeability. Therefore, a training set of 30 structurally diverse compounds with a wide range of inhibitory activity against POP was used to generate a quantitative pharmacophore model, Hypo 3, to identify potential POP inhibitors with desirable drug-like properties. Validations through test set, cost analysis, and Fisher's randomization methods proved that Hypo 3 accurately predicted the known inhibitors among inactive compounds. Hypo 3 was employed as 3D query for virtual screening on an in-house drug-like chemical database containing compounds with good brain permeability and ADMET parameters. Database screening with Hypo 3 resulted in 99 compounds that were narrowed down to 21 compounds through molecular docking. Among them, five compounds were identified in our earlier studies, while two compounds showed in vitro POP inhibition. The current study proposed new 16 virtually screened compounds as potential inhibitors against POP that possess Gold docking score in the range of 64.61-75.74 and Chemscore of -32.25 to -38.35. Furthermore, the top scoring four hit compounds were subjected to molecular dynamics simulations to reveal their appropriate binding modes and assessing binding free energies. The hit compounds interacted with POP effectively via hydrogen bonds with important active site residues along with hydrophobic interactions. Moreover, the hit compounds had key inter-molecular interactions and better binding free energies as compared to the reference inhibitor. A potential new hydrogen bond interaction was discovered between Hit 2 with the Arg252 residue of POP. To conclude, we propose four hit compounds with new structural scaffolds against POP for the lead development of POP-based therapeutics for neurological disorders.

Identification of Novel Scaffolds with Dual Role as Antiepileptic and Anti-Breast Cancer.

Aromatase inhibitors with an $\mathrm{IC}_{50}$ IC 50 value ranging from 1.4 to 49.7 µM are known to act as antiepileptic drugs besides being potential breast cancer inhibitors. The aim of the present study is to identify novel antiepileptic aromatase inhibitors with higher activity exploiting the ligand-based pharmacophore approach utilizing the experimentally known inhibitors. The resultant Hypo1 consists of four features and was further validated by using three different strategies. Hypo1 was allowed to screen different databases to identify lead molecules and were further subjected to Lipinski's Rule of Five and ADMET to establish their drug-like properties. Consequently, the obtained 68-screened molecules were subjected to molecular docking by GOLD v5.2.2. Furthermore, the compounds with the highest dock scores were assessed for molecular interactions. Later, the MD simulation was applied to evaluate the protein backbone stabilities and binding energies adapting GROMACS v5.0.6 and MM/PBSA which was followed by the density functional theory (DFT), to analyze their orbital energies, and further the energy gap between them. Eventually, the number of Hit molecules was culled to three projecting Hit1, Hit2, and Hit3 as the potential lead compounds based on their highest dock scores, hydrogen bond interaction, lowest energy gap, and the least binding energies and stable MD results.

Pharmacotherapeutics and Molecular Mechanism of Phytochemicals in Alleviating Hormone-Responsive Breast Cancer.

Breast cancer (BC) is the leading cause of death among women worldwide devoid of effective treatment. It is therefore important to develop agents that can reverse, reduce, or slow the growth of BC. The use of natural products as chemopreventive agents provides enormous advantages. The aim of the current investigation is to determine the efficacy of the phytochemicals against BC along with the approved drugs to screen the most desirable and effective phytocompound. In the current study, 36 phytochemicals have been evaluated against aromatase to identify the potential candidate drug along with the approved drugs employing the Cdocker module accessible on the Discovery Studio (DS) v4.5 and thereafter analysing the stability of the protein ligand complex using GROningen MAchine for Chemical Simulations v5.0.6 (GROMACS). Additionally, these compounds were assessed for the inhibitory features employing the structure-based pharmacophore (SBP). The Cdocker protocol available with the DS has computed higher dock scores for the phytochemicals complemented by lower binding energies. The top-ranked compounds that have anchored with key residues located at the binding pocket of the protein were subjected to molecular dynamics (MD) simulations employing GROMACS. The resultant findings reveal the stability of the protein backbone and further guide to comprehend on the involvement of key residues Phe134, Val370, and Met374 that mechanistically inhibit BC. Among 36 compounds, curcumin, capsaicin, rosmarinic acid, and 6-shogaol have emerged as promising phytochemicals conferred with the highest Cdocker interaction energy, key residue interactions, stable MD results than reference drugs, and imbibing the key inhibitory features. Taken together, the current study illuminates the use of natural compounds as potential drugs against BC. Additionally, these compounds could also serve as scaffolds in designing and development of new drugs.

Computational Simulations Identify Pyrrolidine-2,3-Dione Derivatives as Novel Inhibitors of Cdk5/p25 Complex to Attenuate Alzheimer's Pathology.

: Mechanistically, neurotoxic insults provoke Ca2+-mediated calpain activation, which cleaves the cytoplasmic region of membrane-embedded p35 and produces its truncated form p25. Upon physical interaction, cyclin-dependent kinase 5 (Cdk5) and p25 forms hyperactivated Cdk5/p25 complex and causes severe neuropathological aberrations including hyperphosphorylated tau-mediated neurofibrillary tangles formation, Alzheimer's symptoms, and neuronal death. Therefore, the inhibition of Cdk5/p25 complex may relieve p-tau-mediated Alzheimer's pathology. Herein, computational simulations have identified pyrrolidine-2,3-dione derivatives as novel inhibitors of Cdk5/p25 complex. A ligand-based pharmacophore was designed and employed as 3D query to retrieve drug-like molecules from chemical databases. By molecular docking, drug-like molecules obtaining dock score > 67.67 (Goldcore of the reference compound) were identified. Molecular dynamics simulation and binding free energy calculation retrieved four pyrrolidine-2,3-dione derivatives as novel candidate inhibitors of Cdk5/p25. The root means square deviation of Cdk5/p25 in complex with candidate inhibitors obtained an average value of ~2.15 Å during the 30 ns simulation period. Molecular interactions analysis suggested that each inhibitor occupied the ATP-binding site of Cdk5/p25 and formed stable interactions. Finally, the binding free energy estimation suggested that each inhibitor had lowest binding energy than the reference compound (-113.10 kJ/mol) to recapitulate their strong binding with Cdk5/p25. Overall, these inhibitors could mitigate tau-mediated Alzheimer's phenotype.

Discovery of Potential Plant-Derived Peptide Deformylase (PDF) Inhibitors for Multidrug-Resistant Bacteria Using Computational Studies.

Bacterial peptide deformylase (PDF) is an attractive target for developing novel inhibitors against several types of multidrug-resistant bacteria. The objective of the current study is to retrieve potential phytochemicals as prospective drugs against Staphylococcus aureus peptide deformylase (SaPDF). The current study focuses on applying ligand-based pharmacophore model (PharmL) and receptor-based pharmacophore (PharmR) approaches. Utilizing 20 known active compounds, pharmL was built and validated using Fischer's randomization, test set method and the decoy set method. PharmR was generated from the knowledge imparted by the Interaction Generation protocol implemented on the Discovery Studio (DS) v4.5 and was validated using the decoy set that was employed for pharmL. The selection of pharmR was performed based upon the selectivity score and further utilizing the Pharmacophore Comparison module available on the DS. Subsequently, the validated pharmacophore models were escalated for Taiwan Indigenous Plants (TIP) database screening and furthermore, a drug-like evaluation was performed. Molecular docking was initiated for the resultant compounds, employing CDOCKER (available on the DS) and GOLD. Eventually, the stability of the final PDF⁻hit complexes was affirmed using molecular dynamics (MD) simulation conducted by GROMACS v5.0.6. The redeemed hits demonstrated a similar binding mode and stable intermolecular interactions with the key residues, as determined by no aberrant behaviour for 50 ns. Taken together, it can be stated that the hits can act as putative scaffolds against SaPDF, with a higher therapeutic value. Furthermore, they can act as fundamental structures for designing new drug candidates.

Investigation of non-hydroxamate scaffolds against HDAC6 inhibition: A pharmacophore modeling, molecular docking, and molecular dynamics simulation approach.

Proteins deacetylation by Histone deacetylase 6 (HDAC6) has been shown in various human chronic diseases like neurodegenerative diseases and cancer, and hence is an important therapeutic target. Since, the existing inhibitors have hydroxamate group, and are not HDAC6-selective, therefore, this study has designed to investigate non-hydroxamate HDAC6 inhibitors. Ligand-based pharmacophore was generated from 26 training set compounds of HDAC6 inhibitors. The statistical parameters of pharmacophore (Hypo1) included lowest total cost of 115.63, highest cost difference of 135.00, lowest RMSD of 0.70 and the highest correlation of 0.98. The pharmacophore was validated by Fischer's Randomization and Test Set validation, and used as screening tool for chemical databases. The screened compounds were filtered by fit value ([Formula: see text]), estimated Inhibitory Concentration (IC[Formula: see text]) ([Formula: see text]), Lipinski's Rule of Five and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Descriptors to identify drug-like compounds. Furthermore, the drug-like compounds were docked into the active site of HDAC6. The best docked compounds were selected having goldfitness score [Formula: see text] and [Formula: see text], and hydrogen bond interaction with catalytic active residues. Finally, three inhibitors having sulfamoyl group were selected by Molecular Dynamic (MD) simulation, which showed stable root mean square deviation (RMSD) (1.6-1.9[Formula: see text]Å), lowest potential energy ([Formula: see text][Formula: see text]kJ/mol), and hydrogen bonding with catalytic active residues of HDAC6.

Targeting natural compounds against HER2 kinase domain as potential anticancer drugs applying pharmacophore based molecular modelling approaches.

Human epidermal growth factor receptors are implicated in several types of cancers characterized by aberrant signal transduction. This family comprises of EGFR (ErbB1), HER2 (ErbB2, HER2/neu), HER3 (ErbB3), and HER4 (ErbB4). Amongst them, HER2 is associated with breast cancer and is one of the most valuable targets in addressing the breast cancer incidences. For the current investigation, we have performed 3D-QSAR based pharmacophore search for the identification of potential inhibitors against the kinase domain of HER2 protein. Correspondingly, a pharmacophore model, Hypo1, with four features was generated and was validated employing Fischer's randomization, test set method and the decoy test method. The validated pharmacophore was allowed to screen the colossal natural compounds database (UNPD). Subsequently, the identified 33 compounds were docked into the proteins active site along with the reference after subjecting them to ADMET and Lipinski's Rule of Five (RoF) employing the CDOCKER implemented on the Discovery Studio. The compounds that have displayed higher dock scores than the reference compound were scrutinized for interactions with the key residues and were escalated to MD simulations. Additionally, molecular dynamics simulations performed by GROMACS have rendered stable root mean square deviation values, radius of gyration and potential energy values. Eventually, based upon the molecular dock score, interactions between the ligands and the active site residues and the stable MD results, the number of Hits was culled to two identifying Hit1 and Hit2 has potential leads against HER2 breast cancers.