Aarti Singh

Pharmacophore based virtual screening, molecular docking and biological evaluation to identify novel PDE5 inhibitors with vasodilatory activity

Prompted by the role of PDE5 and its closely associated cAMP and cGMP in hypertension, we have attempted to discover novel PDE5 inhibitors through ligand based virtual screening. Rigorously validated model comprising of one HBA, one HY and one RA was used as a query to search the NCI database leading to retrieval of many compounds which were screened on the basis of estimated activity, fit value and Lipinskis violation. Selected compounds were subjected to docking studies which resulted into visualization of potential interaction capabilities of NCI compounds in line to pharmacophoric features. Finally three compounds were subjected to in vitro evaluation using the isolated rat aortic model. The results showed that all three compounds are potent and novel PDE5 inhibitors with vasodilatory activity range from 10(-2) to 10(-5) M.

In silico and in vitro screening to identify structurally diverse non-azole CYP51 inhibitors as potent antifungal agent

The problem of resistance to azole class of antifungals is a serious cause of concern to the medical fraternity and thus there is an urgent need to identify non-azole scaffolds with high affinity for lanosterol 14α-demethylase (CYP51). In view of this we have attempted to identify novel non-azole CYP51 inhibitors through the application of pharmacophore based virtual screening and in vitro evaluation. A rigorously validated pharmacophore model comprising of 2 hydrogen bond acceptor and 2 hydrophobic features has been developed and used to mine NCI database. Out of 265 retrieved hits, NSC 1215 and 1520 have been chosen on the basis of Lipinskis rule of five, fit and estimated values. Both the hits were docked into the active site of CYP51. In view of high fit value and CDocker score, NSC 1215 and 1520 have been subjected to in vitro microbiological assay. The result reveals that NSC 1215 and 1520 are active against Candida albicans, Candida parapsilosis, Candida tropicalis, and Aspergillus niger. In addition to this the absorption characteristics of both the hits have also been determined using the rat sac technique and permeation in order of NSC 1520>NSC 1215 has been observed.

Identification of novel antifungal lead compounds through pharmacophore modeling, virtual screening, molecular docking, antimicrobial evaluation, and gastrointestinal permeation studies

Identification of novel antifungal lead compounds through pharmacophore modeling, virtual screening, molecular docking, antimicrobial evaluation, and gastrointestinal permeation studies Aarti Singh, Sarvesh Paliwal*, Mukta Sharma, Anupama Mittal, Swapnil Sharma, Neetika Tripathi and Amita Tilak Department of Pharmacy, Banasthali University, Banasthali, Rajasthan 304022, India; Department of Pharmacy, GSVM Medical College, Swaroop Nagar, Kanpur, Uttar Pradesh 208002, India

Pharmacophore and molecular docking based identification of novel structurally diverse PDE-5 inhibitors

In view that PDE5 is a potential target for the design of antihypertensive drugs a pharmacophore and molecular docking based virtual screening protocol was implemented. Two hydrophobic and one ring aromatic feature containing pharmacophore model was developed, validated, and used to mine Maybridge chemical compound database. This led to retrieval of many hits which were screened on the basis of estimated activity, fit value, and Lipinski’s violation. The eight selected hits were docked into the active site of PDE5 to evaluate the specific inhibitor-enzyme interactions finally leading to identification of two potent, druggable PDE5 inhibitors with good LibDock scores. Both the compounds showed interaction with Gln 817, Tyr 612, and Ala 767 amino acid residues testifying the results obtained from pharmacophore modeling.

Fluoride: A review of pre-clinical and clinical studies

Fluoride is ubiquitous in environment and profound in bones, teeth and calcified tissues of human body. Fluoride has been the topic of regular discussion and investigations. Besides its toxicity, fluoride has also been examined for its beneficial effects like prevention and treatment of tooth decay, microbial infection, inflammation, cancer, occurrence of renal stone and many more. Since last many decades, several efforts have been made at pre-clinical and clinical level to understand role of fluoride in biological system. The present review gives a brief account of prevalence, sources of fluoride toxicity and pre-clinical and clinical studies carried out on effects of fluoride in last six decades.

Identification of novel and structurally diverse N-Methyl-D-Aspartate Receptor Antagonists: Successful Application of Pharmacophore Modeling, Virtual Screening and Molecular Docking

In view of “excitotoxic” effects of glutamate, wherein excessive excitatory input causes increase in intracellular Ca2+ and ultimately cell death, NMDA receptor has emerged as an important target for treatment and prevention of several neurological disorders, like Alzheimer disease. Prompted by the successful application of in-silico pharmacophore-based virtual screening in lead identification, we have made an effort to implement in-silico protocols to identify novel NMDA receptor antagonist. A series of novel benzo[b]quinolizinium cations as NMDA receptor antagonists have been used as a starting point to develop prognostic pharmacophore models. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, one hydrogen bond acceptor, one hydrophobic and two ring aromatic, showed a correlation (r) of 0.89, root mean square of 0.259, and the cost difference of 43.01 bits between null and fixed cost. The model was thoroughly validated and subjected to a chemical database search, which lead to the identification of 400 hits from NCI and Maybridge databases which were checked for Lipinski’s violation and predictive potency. This reduced the list to 10 compounds, out of which, two most potent compounds were subjected to molecular docking using Libdock software and interestingly, all the docked conformations showed hydrogen bond interactions with important amino acids Tyr214, His88, Thr174, Val169 and Arg121. In summary, through our validated pharmacophore-based virtual screening protocol, we have identified two potent, structurally diverse, druggable and novel NMDA receptor antagonist which might be of great help to address the unmet medical need of Alzheimer disease.

Pharmacophore-driven Identification of N-Methyl-D-Receptor Antagonists as Potent Neuroprotective Agents Validated Using In-Vivo Studies

Alzheimer’s disease (AD), the most widespread cause of dementia is delineated by progressive cognitive impairment in the elderly people. During its progression, N-Methyl-D-Aspartate receptor antagonists are known to play a key role in the mechanisms of learning and memory. Extensive side effects alongside other effects on learning and memory have limited the therapeutic significance of various blockers and antagonists of the NMDA receptor. In this study, we identify potential compounds targeted against NMDA. In order to reveal the essential structural features for NMDA receptor, three-dimensional pharmacophore models are constructed based on a set of known NMDA inhibitors. This is followed by virtual screening which results in novel chemical compounds having the potential to inhibit NMDA. The lead compounds are then subjected to molecular docking and assessed by a scoring function, which results in two compounds with high Libdock scores. These compounds also show interactions with important residues at the active site. The compounds are shortlisted on the basis of high estimated activity, fit values, LibDock score, no violation to Lipinski’s and availability for procuring. Of the shortlisted compounds, one compound satisfying the entire aforementioned criterion is further tested using in-vivo studies on mice with the help of an eight-arm radial maze. The pharmacophore-based virtual screening protocol presented in this study pave the way forward to address the unmet medical need of Alzheimer disease.

Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators

In view of the role of sEH (soluble epoxide hydrolase) in hypertension, we have developed a rigorously validated pharmacophore model containing one HBA (Hydrogen Bond Acceptor), two HY (Hydrophobic) and one RA (Ring Aromatic) features. The model was used as a query to search the NCI (National Cancer Institute) and Maybridge database leading to retrieval of many compounds which were sorted on the basis of predicted activity, fit value and Lipinski’s violation. The selected compounds were docked into the active site of enzyme soluble epoxide hydrolase. Potential interactions were observed between the features of the identified hits and the amino acids present in the docking site. The three selected compounds were subjected to in vitro evaluation using enzyme- based assay and the isolated rat aortic model followed by cytotoxicity studies. The results demonstrate that the identified compounds are potent, safe and novel soluble epoxide hydrolase inhibitors.

The Synthetic and Biological Attributes of Pyrazole Derivatives: A Review

Pyrazole nucleus is a unique structural scaffold which acts as an interesting template for combinatorial as well as medicinal chemistry. This review presents a detailed overview on the synthesis, QSAR and pharmacological applications of pyrazole. In addition, it covers most recent reports on structural modifications on pyrazole illustrating vital structural activity relationship.