Shailendra Paliwal

Development of a robust QSAR model to predict the affinity of pyrrolidine analogs for dipeptidyl peptidase IV (DPP- IV)

QSAR analysis using multiple linear regression and partial least squares methods were conducted on a data set of 47 pyrrolidine analogs acting as DPP IV inhibitors. The QSAR models generated (both MLR and PLS) were robust with statistically significant s, F, r, r2 and r2 (CV) values. The analysis helped to ascertain the role of shape flexibility index, Ipso atom E-state index and electrostatic parameters like dipole moment, in determining the activity of DPP IV inhibitors. In addition to QSAR modeling, Lipinski’s rule of five was also employed to check the pharmacokinetic profile of DPP IV inhibitors. Since none of the compounds violated the Lipinski’s rule of five indicating that the DPP IV inhibitors reported herein have sound pharmacokinetic profile and can be considered as potential drug candidates for diabetes mellitus Type II.

Neglected disease - african sleeping sickness: recent synthetic and modeling advances.

Human African Trypanosomiasis (HAT) also called sleeping sickness is caused by subspecies of the parasitic hemoflagellate Trypanosoma brucei that mostly occurs in sub-Saharan Africa. The current chemotherapy of the human trypanosomiases relies on only six drugs, five of which have been developed more than 30 years ago, have undesirable toxic side effects and most of them show drug-resistance. Though development of new anti-trypanosomal drugs seems to be a priority area research in this area has lagged far behind. The given review mainly focus upon the recent synthetic and computer based approaches made by various research groups for the development of newer anti-trypanosomal analogues which may have improved efficacy and oral bioavailability than the present ones. The given paper also attempts to investigate the relationship between the various physiochemical parameters and anti-trypanosomal activity that may be helpful in development of potent anti-trypanosomal agents against sleeping sickness.

In silico structure-based drug design approach to develop novel pharmacophore model of human peroxisome proliferator-activated receptor γ agonists

A structure-based pharmacophore generation approach was employed to identify novel structural characteristics and scaffolds for peroxisome proliferator-activated receptor γ (PPARγ). The structure-based six feature pharmacophore hypothesis generated in the present study signifies the importance of hydrogen bond donors, hydrogen bond acceptors and hydrophobic interaction between the PPARγ structure and its agonists. The interaction shown by the compounds provides an important insight into the mechanism involved in the ligand receptor interaction. The model will aid in the development of oral hypoglycemic agents with improved efficacy and reduced side effects and can be used to search comparatively larger compound libraries/databases to retrieve more potent and structurally diverse group of compounds.

Entrapment of ketorolac tromethamine in polymeric vehicle for controlled drug delivery.

The most common method for applying a drug in to the eye is to formulate the drug in the form of an eye drop, but this method is not considered ideal for ocular delivery of drug because of poor bioavailability arising from precorneal loss processes, this loss of drug from the precorneal area is a net effect of drainage, tear secretion and noncorneal absorption. Following the above lead we tried to improve the ocular bioavailability by increasing the corneal contact time and the feasible way was to formulate a drug with mucoadhesive/viscosity imparting agents. The adhesive strength of various polymers on corneal surface was studied with the help of self modified Franz diffusion cell and freshly excised goat/bovine cornea. The polymers hydroxypropylmethylcellulose, carboxymethylcellulose sodium, Eudragit type E/RL/RS, Carbopol ETD 2020 and Carbopol 934 National Formulary were formulated with drug, ketorolac tromethamine. The adhesive strength of polymers on corneal surface and permeation characteristics of drug through cornea were investigated by using above said formulations. Eudragit type E/RL/RS did not show any improvement in mucoadhesion, but the formulations containing Carbopol ETD 2020 and Carbopol 934 national formulary showed good mucoadhesion on corneal surface in the concentration as low as 0.75%. The mucoadhesive strength was also evaluated using the combination of Carbopol acrylates/C 10-30 alkylacrylate with allylpentaerithrital and preservative benzalkonium chloride, which also resulted in good mucoadhesion with improved corneal permeation. Observations made in this study indicate the potentiality of the ophthalmic formulations containing mucoadhesive/viscosity imparting agents.

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.

Chemical Feature-Based Molecular Modeling of Urotensin-II Receptor Antagonists: Generation of Predictive Pharmacophore Model for Early Drug Discovery

For a series of 35 piperazino-phthalimide and piperazino-isoindolinone based urotensin-II receptor (UT) antagonists, a thoroughly validated 3D pharmacophore model has been developed, consisting of four chemical features: one hydrogen bond acceptor lipid (HBA_L), one hydrophobe (HY), and two ring aromatic (RA). Multiple validation techniques like CatScramble, test set prediction, and mapping analysis of advanced known antagonists have been employed to check the predictive power and robustness of the developed model. The results demonstrate that the best model, Hypo 1, shows a correlation (r) of 0.902, a root mean square deviation (RMSD) of 0.886, and the cost difference of 39.69 bits. The model obtained is highly predictive with good correlation values for both internal () as well as external () test set compounds. Moreover, the pharmacophore model has been used as a 3D query for virtual screening which served to detect prospective new lead compounds which can be further optimized as UT antagonists with potential for treatment of cardiovascular diseases.

Common binding requirements of PPAR-α/δ/γ pan agonists: quantitative structure–activity relationship analysis of indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail group

A QSAR study on a series of indanylacetic acid derivatives with activity against PPAR-α, δ, and γ was made using combination of various physiochemical descriptors. Several statistical regression expressions were obtained using stepwise multiple linear regression (MLR) analysis and partial least square (PLS) method. The highly predictive and validated models generated through classical 2D molecular descriptors provided deeper insights about the binding of these small molecules to the human nuclear receptor PPAR-α, δ, and γ. The results reveal that dipole moment and number of hydrogen bond donors are important descriptors in determining effective binding of PPAR agonists to all three subtypes.

Quantitative structure activity relationship (QSAR) of N6-substituted adenosine receptor agonists as potential antihypertensive agents

Quantitative structure activity relationship studies are indubitably of great importance in modern chemistry. In pursuit of better antihypertensive agents, QSAR studies were performed on a series of 48 N6-substituted adenosines analogs. The models were developed using multiple linear regression (MLR) and partial least square (PLS) with many descriptors like electronic, topological, and lipophilic. QSAR models were evaluated for statistical significance and predictive power. The MLR and PLS generated comparable results with good predictive ability and all the other statistical values such as r, r2, rcv2, F, and s values were 0.92, 0.84, 0.83, 61.74, 0.24, respectively, for MLR and rcv2 and statistical significance values of 0.82 and 0.80, respectively, for PLS were satisfactory. The model indicates that the Verloop L, total lipole, VAMP nuclear energy, plays an important role in determining the antihypertensive activity of N6-substituted adenosine receptor agonists. The model developed in the present study will be useful in the design of more potent N6-substituted adenosine receptor agonists as antihypertensive agent.

A QSAR Study Investigating the Potential Anti-Leishmanial Activity of Cationic 2-Phenylbenzofurans

The QSAR models were developed using multiple linear regression (MLR) and partial least squares (PLS) for 41 2-phenylbenzofurans derivatives against leishmania donovani. The MLR and PLS generated comparable models with good predictive ability and all other statistical values, r, r2, r2 cv, r2 (test set) and F and S values, were 0.86, 0.74, 0.72, 0.70 and 38.56, 0.28, respectively, for MLR and r2 cv, r2 (test set) and statistical significance value were 0.71, 0.70 and 0.99, respectively, for PLS, were satisfactory. The results indicate the importance of dipole moment and Kier Chi in determining the activity of 2-phenylbenzofurans as potent antiprotozoal agents.

QSAR Analysis of Anti-Toxoplasma Agents

The QSAR models were developed using multiple linear regression (MLR) and partial least square (PLS) for 2, 4-diamino-8-deazafolate analogues generated comparable models with good predictive ability and all other statistical values, r, r2, r2 cv, r2 (test set) F and s values were 0.94, 0.88, 0.86, 0.84, 58.70 and 0.13 respectively for MLR and r2 cv, r2 (test set) and statistical significance values were 0.87, 0.84 and 0.99 respectively for PLS, were satisfactory. The analysis indicate the role of first atom E-state, number of H-bond doners and VAMP mean polarizability in determining the activity of 2, 4-diamino-8-deazafolate analogues as potent antitoxoplasmal agents.