Shubham Srivastava

Febrifugine analogues as Leishmania donovani trypanothione reductase inhibitors: binding energy analysis assisted by molecular docking, ADMET and molecular dynamics simulation

Visceral leishmaniasis affects people from 70 countries worldwide, mostly from Indian, African and south American continent. The increasing resistance to antimonial, miltefosine and frequent toxicity of amphotericin B drives an urgent need to develop an antileishmanial drug with excellent efficacy and safety profile. In this study we have docked series of febrifugine analogues (n = 8813) against trypanothione reductase in three sequential docking modes. Extra precision docking resulted into 108 ligands showing better docking score as compared to two reference ligand. Furthermore, 108 febrifugine analogues and reference inhibitor clomipramine were subjected to ADMET, QikProp and molecular mechanics, the generalized born model and solvent accessibility study to ensure the toxicity caused by compounds and binding-free energy, respectively. Two best ligands (FFG7 and FFG2) qualifying above screening parameters were further subjected to molecular dynamics simulation. Conducting these studies, here we confirmed that 6-chloro-3-[3-(3-hydroxy-2-piperidyl)-2-oxo-propyl]-7-(4-pyridyl) quinazolin-4-one can be potential drug candidate to fight against Leishmania donovani parasites.

Exploring dual inhibitory role of febrifugine analogues against Plasmodium utilizing structure-based virtual screening and molecular dynamic simulation

Malaria is an endemic disease caused by the protozoan parasite Plasomodium falciparum. Febrifugine analogues are natural compound obtained from the traditional Chinese herbs have shown significant antimalarial and anticancerous efficacy in experimental model. Development of resistance against the existing antimalarial drug has alarmed the scientific innovators to find a potential antimalarial molecule which can be further used by endemic countries for the elimination of this disease. In this study, structure-based virtual screening and molecular dynamics (MD) base approaches were used to generate potential antimalarial compound against plasmepsin II and prolyl-tRNA synthetase of Plasmodium. Here, we have docked series of febrifugine analogues (n = 11,395) against plasmepsin II in three different docking modes and then it was compared with previously reported target prolyl-tRNA synthetase. Extra precision docking resulted into 235 ligands having better docking score were subject for QikProp analysis. Better ligands (n = 39) obtained from QikProp analysis were subject for ADMET prediction and docking protocol validation through the estimation of receiver operator characteristics. In the later stage, 24 ligands obtained from ADMET study were subject for the estimation of binding energy through MM-GBSA and same were also docked against prolyl-tRNA synthetase to get compounds with dual inhibitor role. Finally, MD simulation and 2D fingerprint MACCS study of two best ligands have shown significant interaction with plasmepsin II and homology against known active ligand with noteworthy MACCS index, respectively. This study concludes that FA12 could be potential drug candidate to fight against Plasmodium falciparum parasites.

Identification of novel acetylcholinesterase inhibitors through e-pharmacophore-based virtual screening and molecular dynamics simulations

Alzheimer’s disease (AD), a progressive neurodegenerative disorder is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine via inhibiting acetylcholinesterase (AChE). The present study involves identification of newer AChE inhibitors by dual approach of e-pharmacophore and structure-based virtual screening of Asinex library. Robustness of docking protocol was validated by enrichment calculation with ROC value .71 and BEDROC value .028. Among 11 selected hits, ZINC72338524 with best MM-GBSA dG binding shows optimal range of CNS properties and ligand–AChE complex stability. Further, molecular dynamics study revealed its molecular interactions with Trp86, Phe338, and Tyr341 amino acid residues of catalytic anionic site and Tyr124, Ser125, and Trp286 amino acid residues of peripheral anionic site. Physicochemical properties and ADMET risk prediction indicates their potential in druggability and safety.

Design, synthesis and biological evaluation of selected 3-[3-(amino) propoxy] benzenamines as acetylcholinesterase inhibitors

The present paper describes design, synthesis, and biological evaluation of a series of some 3-[3-(amino)propoxy]benzenamines as acetylcholinesterase inhibitors using mice as a model and piracetam as a reference drug. The structures of these compounds were confirmed by spectral analysis and compounds were tested for memory enhancing activity using elevated plus maze test and acetylcholinesterase inhibitory assay. The inhibitory range of synthesized compounds was from 8.99 to 28.31 μM. The synthesized compounds possessed higher or equivalent percent retention as compared to piracetam at 1 mg/kg with no other CNS-related activities (locomotor and muscle relaxant, analgesic and anticonvulsant activities). Compound 3-[3-(imidazolo)propoxy]benzenamine has shown significant dose-dependent (1 and 3 mg/kg) memory enhancing activity, while 3-[3-(pyrrolidino)propoxy]benzenamine also showed activity equivalent to reference drug piracetam at 1 mg/kg. Both compounds 3-[3-(pyrrolidino)propoxy]benzenamine and 3-[3-(imidazolo)propoxy]benzenamine were also found to show AChE inhibition with IC50 value of 8.99 and 17.87 μM. The molecular docking, MM-GBSA and molecular dynamics simulation studies were performed in order to establish a relationship between the biological results. RMSD, root-mean-square fluctuations, and interaction patterns of 10a–AChE and Sck–AChE complexes proved that the binding affinity of 10a toward AChE was highly stable with the proposed binding orientations.

Structure-based screening, ADMET profiling, and molecular dynamic studies on mGlu2 receptor for identification of newer antiepileptic agents

Structure-based screening approach targeting mGlu2 receptor was carried out to identify good chemical starting points for anti-epileptic therapy. Interactive modes of final 12 compounds identified on the basis of screening of Asinex library, binding energy analysis, ADME profiling with special emphasis for CNS ranges, and toxicity analysis were studied and showed good binding modes in the mGluR2-active site. Enrichment studies for validating screening protocol were carried out which gave ROC values 0.98 (AUC = 0.96) for SP, 0.97 (AUC = 0.95) for XP with BEDROC analysis. Our results indicate that all the 12 hits showed good CNS drug-like properties, have better binding free energy and ADME profile as compared to co-crystallized ligand with the best ligand hit retaining conserved hydrogen bond interactions with Ala-166, Thr-168, Ser-145, and Arg-61 residues in bilobatevenus fly-trap domain of mGluR2 receptor. Molecular dynamics simulations proved that the two potential hits, qualifying all screening parameters, are stable in the receptor active site pocket, confirming the potential of the identified hits as a specific target for mGluR2. Because the newly discovered mGluR2 agonists are structurally different with Tc values ranging from 0.57 to 0.92, all of them can be considered for further de novo design methods.

Polypropyleneimine and polyamidoamine dendrimer mediated enhanced solubilization of bortezomib: Comparison and evaluation of mechanistic aspects by thermodynamics and molecular simulations

Bortezomib (BTZ) is the first proteasome inhibitor approved by the US-FDA is majorly used for the treatment of newly diagnosed and relapsed multiple myeloma including mantle cell lymphoma. BTZ is hydrophobic in nature and is a major cause for its minimal presence as marketed formulations. The present study reports the design, development and characterization of dendrimer based formulation for the improved solubility and effectivity of bortezomib. The study also equally focuses on the mechanistic elucidation of solubilization by two types of dendrimers i.e. fourth generation of poly (amidoamine) dendrimers (G4-PAMAM-NH2) and fifth generation of poly (propylene) imine dendrimers (G5-PPI-NH2). It was observed that aqueous solubility of BTZ was concentration and pH dependent. At 2mM G5-PPI-NH2 concentration, the fold increase in bortezomib solubility was 1152.63 times in water, while approximately 3426.69 folds increase in solubility was observed at pH10.0, respectively (p<0.05). The solubility of the drug was increased to a greater extent with G5-PPI-NH2 dendrimers because it has more hydrophobic interior than G4-PAMAM-NH2 dendrimers. The release of BTZ from G5-PPI-NH2 complex was comparatively slower than G4-PAMAM-NH2. The thermodynamic treatment of data proved that dendrimer drug complexes were stable at all pH with values of ΔG always negative. The experimental findings were also proven by molecular simulation studies and by calculating RMSD and intermolecular hydrogen bonding through Schrodinger software. It was concluded that PPI dendrimers were able to solubilize the drug more effectively than PAMAM dendrimers through electrostatic interactions.

Pharmacophore modeling, 3D-QSAR, and in silico ADME prediction of N-pyridyl and pyrimidine benzamides as potent antiepileptic agents

Abstract Biological mechanism attributing mutations in KCNQ2/Q3 results in benign familial neonatal epilepsy (BFNE), a rare form of epilepsy and thus neglected. It offers a potential target for antiepileptic drug discovery. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of N-pyridyl and pyrimidine benzamides possessing KCNQ2/Q3 opening activity. The pharmacophore model generated contains one hydrogen bond donor (D), one hydrophobic (H), and two aromatic rings (R). They are the crucial molecular write-up detailing predicted binding efficacy of high affinity and low affinity ligands for KCNQ2/Q3 opening activity. Furthermore, it has been validated by using a biological correlation between pharmacophore hypothesis-based 3D-QSAR variables and functional fingerprints of openers responsible for the receptor binding and also by docking of these benzamides into the validated homology model. Excellent statistical computational tools of QSAR model such as good correlation coefficient (R2 > 0.80), higher F value (F > 39), and excellent predictive power (Q2 > 0.7) with low standard deviation (SD <0.3) strongly suggest that the developed model could be used for prediction of antiepileptic activity of newer analogs. A preliminary pharmacokinetic profile of these derivatives was also performed on the basis of QikProp predictions.

Probing voltage sensing domain of KCNQ2 channel as a potential target to combat epilepsy: a comparative study

Abstract Multidrug resistance along with side-effects of available anti-epileptic drugs and unavailability of potent and effective agents in submicromolar quantities presents the biggest therapeutic challenges in anti-epileptic drug discovery. The molecular modeling techniques allow us to identify agents with novel structures to match the continuous urge for its discovery. KCNQ2 channel represents one of the validated targets for its therapy. The present study involves identification of newer anti-epileptic agents by means of a computer-aided drug design adaptive protocol involving both structure-based virtual screening of Asinex library using homology model of KCNQ2 and 3D-QSAR based virtual screening with docking analysis, followed by dG bind and ligand efficiency calculations with ADMET studies, of which 20 hits qualified all the criterions. The best ligands of both screenings with least potential for toxicity predicted computationally were then taken for molecular dynamic simulations. All the crucial amino acid interactions were observed in hits of both screenings such as Glu130, Arg207, Arg210 and Phe137. Robustness of docking protocol was analyzed through Receiver operating characteristic (ROC) curve values 0.88 (Area under curve AUC = 0.87) in Standard Precision and 0.84 (AUC = 0.82) in Extra Precision modes. Novelty analysis indicates that these compounds have not been reported previously as anti-epileptic agents. Graphical Abstract

Identification of chemically diverse GABAA agonists as potential anti-epileptic agents using structure-guided virtual screening, ADMET, quantum mechanics and clinical validation through off-target analysis

Development of resistance against existing anti-epileptic drugs has alarmed the scientific innovators to find novel potential chemical starting points for the treatment of epilepsy and GABAA inhibition is a promising drug target strategy against epilepsy. The crystal structure of a subtype-selective β3-homopentameric ligand-gated ion channel of GABAA receptor has been used for the first time for screening the Asinex library for discovery of GABAA agonists as potential anti-epileptic agents. Co-crystallized ligand established the involvement of part of the β7-β8 loop (Glu155 and Tyr157) and β9-β10 loop (Phe200 and Tyr205) residues as the crucial amino acids in effective binding, an essential feature, being hydrogen bond or ionic interaction with Glu155 residue. Top ranked hits were further subjected to binding energy estimation, ADMET analysis and ligand efficiency matric calculations as consecutive filters. About 19 compounds qualifying all parameters possessed interaction of one positively charged group with Glu155 with good CNS drug-like properties. Simulation studies were performed on the apo protein, its complex with co-crystallized ligand and the best hit qualifying all screening parameters. The best hit was also analyzed using Quantum mechanical studies, off-target analysis and hit modification. The off-target analysis emphasized that these agents did not have any other predicted side-effects.

2-(chromon-3-yl)imidazole derivatives as potential antimicrobial agents: synthesis, biological evaluation and molecular docking studies

A series of novel 2-(chromon-3-yl)-4,5-diphenyl-1H-imidazoles (4a-h) were synthesized by one pot condensation of substituted 3-formylchromones (1a-h), benzil (2) and ammonium acetate (3) in refluxing acetic acid at 110 °C under N2 atmosphere. Allylation of compounds 4a-h with allyl bromide in the presence of fused K2CO3 furnished N-allyl-2-(chromon-3-yl)-4,5-diphenyl-1H-imidazoles (6a-h). The synthesized compounds were characterized spectroscopically and evaluated for in vitro antimicrobial activity against various pathogenic bacterial and fungal strains by disc diffusion method. Compounds bearing electron withdrawing substituents such as bromo (4f) showed significant inhibitory activity against S. cerevisiae (MIC 1.4 μg/ml) and 4g containing chloro substituent, displayed more inhibitory potential against C. albicans (MIC 1.5), as compared to the standard drugs. Compounds 6a and 4c exhibit remarkable inhibitory potential against B. subtilis with MIC 0.98 and 1.23, respectively. The time kill assay for active compound 6a was performed by viable cell count (VCC) method to elucidate the microbicidal nature of 2-(chromon-3-yl)imidazoles. A molecular docking study of most active compounds with target ‘lanosterol 14α-demethylase’ (CYP51) was performed to unravel the mode of antifungal action.