Exploring the Molecular Structural Requirements of Flavonoids as Beta- Secretase-1 Inhibitors Using Molecular Modeling Studies.

BACKGROUND: BACE1 (beta-site amyloid precursor protein (APP) cleaving enzyme) is a key target for Alzheimer's disease research because it catalyses the rate-limiting step in the formation of amyloid protein (Aß). Natural dietary flavonoids have gained a lot of interest as potential Alzheimer's therapy candidates because of their anti-amyloidogenic, antioxidative, and anti-inflammatory properties. More research is needed, however, to learn more about the specific routes through which flavonoids may have neuroprotective benefits in Alzheimer's disease. OBJECTIVE: Here, we report an in silico molecular modeling study for natural compounds, particularly flavonoids, as BACE-1 inhibitors. METHODS: The interactions of flavonoids with the BACE-1 catalytic core were disclosed by demonstrating the predicted docking pose of flavonoids with BACE-1. The stability of flavonoids BACE-1 complex was analyzed by molecular dynamic simulation (standard dynamic cascade). RESULTS: Our findings imply that these flavonoids, which have methoxy group instead of hydroxy may be promising BACE1 inhibitors that could reduce Aß formation in Alzheimer's disease. The molecular docking study revealed that flavonoids e bind with the BACE1's wide active site along with the catalytic residues Asp32 and Asp228. Further molecular dynamic investigation revealed that the average RMSD for all complexes ranged from 2.05 to 2.32 Å, indicating that the molecules were relatively stable during MD simulation. The RMSD analyses demonstrate that the flavonoids were structurally stable during the MD simulation. The RMSF was utilised to study the time-dependent fluctuation of the complexes. The N-terminal (~2.5 Å) fluctuates less than the C-terminal (~6.5 Å). Rutin and Hesperidin were highly stable in the catalytic region as compared to other flavonoids like Rhoifolin, Hesperidin, Methylchalcone, Phlorizin and Naringin. CONCLUSION: We were able to justify the flavonoids' selectivity for BACE-1 and crossing BBB for the treatment of Alzheimer's disease by using a combination of molecular modelling tools.

Synthesis and Anticancer Activity of Thiadiazole Containing Thiourea, Benzothiazole and Imidazo[2,1-b][1,3,4]thiadiazole Scaffolds.

BACKGROUND: A great array of nitrogen-containing heterocyclic rings were being extensively explored for their functional versatility in the field of medicine, especially in anticancer research. 1,3,4- thiadiazole is one of such heterocyclic rings with promising anticancer activity against several cancer cell lines, inhibiting diverse biological targets. INTRODUCTION: The 1,3,4-thiadiazole, when equipped with other heterocyclic scaffolds, has displayed enhanced anticancer properties. The thiourea, benzothiazole, imidazo[2,1,b][1,3,4]-thiadiazoles are such potential scaffolds with promising anticancer activity. METHODS: A new series of 5-substituted-1,3,4-thiadiazoles linked with phenyl thiourea, benzothiazole and 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized and tested for invitro anticancer activity on various cancer cell lines. RESULTS: The National Cancer Institute's preliminary anticancer screening results showed compounds 4b and 5b having potent antileukemic activity. Compound 4b selectively showed 32 percent lethality on Human Leukemia-60 cell line. The docking studies of the derivatives on aromatase enzyme (Protein Data Bank: 3S7S) have shown reversible interactions at the active site with good docking scores comparable to Letrozole and Exemestane. Furthermore, the selected derivatives were tested for anticancer activity on HeLa cell line based on the molecular docking studies. CONCLUSION: Compounds 4b and 5b showed effective inhibition equivalent to Letrozole. These preliminary biological screening studies have given positive anticancer activity for these new classes of derivatives. An additional research study like the mechanism of action of the anticancer activity of this new class of compounds is necessary. These groundwork studies illuminate a future pathway for research of this class of compounds enabling the discovery of potent antitumor agents.

A review of pharmacological and clinical studies on the application of Shenling Baizhu San in treatment of Ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: The prescription of Shenling Baizhu San (SLBZS) was derived from the Song Dynasty "Taiping Huimin Heji Ju Fang", which was a representative prescription for treating spleen asthenic diarrhea. The prescription comprised of 10 herbs for treating weak spleen and stomach. It describes symptoms like eating less, loose stools, cough, shortness of breath and tired limbs. SLBZS has been reported to be capable of eliminating discomfort when it is administered for treating irritable bowel syndrome and diarrhea. This traditional Chinese medicine (TCM) formula has been widely used for improving gastrointestinal dysfunction and modifying the immune response to inflammation. AIM OF THE STUDY: This review is aimed to provide the up-to-date information on the pharmacology and clinical research of SLBZS in the treatment of ulcerative colitis (UC), and to discuss the research findings and possible deficiencies, hoping to better guide the clinical application and scientific research of SLBZS in the treatment of UC. MATERIALS AND METHODS: Relevant studies from 2004 to 2018 on SLBZS in the treatment of UC mechanism and curative effect were collected from ancient books, pharmacopoeia, reports, thesis via library and Digital databases (PubMed, CNKI, Google Scholar, Web of Science, SciFinder, Springer, Elsevier, etc). RESULTS: SLBZS could regulate inflammatory factors and intestinal flora, and ERK/p38 MAPK signaling pathway may be one of its targets. In addition, clinical research results show that SLBZS has a good therapeutic effect on UC, and the adverse reactions are small. CONCLUSION: Although SLBZS has achieved some success in the treatment of UC, there are still some scientific gaps. There is a lack of uniform standards for constructing UC animal models, and some methods of modeling through environmental and dietary interventions are not reproducible, and there is a lack of uniform dosing regimen standards. SLBZS doses follow the tradition and lack toxicological validation. Therefore, more specific toxicological research models are essential. The clinical application of SLBZS requires reassessment and standardization. Although all clinical research reports randomly assigned patients to different groups, most did not describe a detailed method of randomization and no description of the analysis data. In addition, extensive in vitro studies and further in-depth molecular studies are essential for the determination of mechanisms that have been performed in all in vivo experiments on animal models and patients.

Aromatase Inhibitors Evolution as Potential Class of Drugs in the Treatment of Postmenopausal Breast Cancer Women.

Aromatase inhibitors are class of drugs that inhibit aromatase, a rate limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Estrogens play a vital role in the development and growth of breast tumors especially in postmenopausal women apart from their important functions in cell homeostasis. The reduction of estrogen physiological concentration through aromatase inhibition is one of the most important therapeutic strategies against this cancer type. The third-generation aromatase inhibitors are now used as first-line therapy in the treatment of early and metastatic breast cancer in postmenopausal women. However the quest for new class of drugs still stays indispensable to evade the danger of conceivable rising resistances to existing drugs, toxicity and unwanted side effects due to chronic treatment. The current review deals with recent advances in understanding of aromatase, its mechanism and research in the development of various novel chemotypes as aromatase inhibitors. The new challenges and the fast changing trends in bringing rational approach in aromatase inhibitors to a different level like research in dual/multiple target enzyme inhibition strategies, radiolabeling of aromatase inhibitors as theranostic agents; the development of new computational models for complete understanding of aromatase enzyme and its substrate/ligand interactions will bring in holistic approach to comprehensive inhibition of aromatase and other relevant enzymes for effective treatment and monitoring of postmenopausal breast cancer.

Polymeric micelles: Basic research to clinical practice.

Rapidly developing polymeric micelles as potential targeting carriers has intensified the need for better understanding of the underlying principles related to the selection of suitable delivery materials for designing, characterizing, drug loading, improving stability, targetability, biosafety and efficacy. The emergence of advanced analytical tools such as fluorescence resonance energy transfer and dissipative particle dynamics has identified new dimensions of these nanostructures and their behavior in much greater details. This review summarizes recent efforts in the development of polymeric micelles with respect to their architecture, formulation strategy and targeting possibilities along with their preclinical and clinical aspects. Literature of the past decade is discussed critically with special reference to the chemistry involved in the formation and clinical applications of these versatile materials. Thus, our main objective is to provide a timely update on the current status of polymeric micelles highlighting their applications and the important parameters that have led to successful delivery of drugs to the site of action.

In silico Evidence for Binding of Pentacyclic Triterpenoids to Keap1-Nrf2 Protein-Protein Binding Site.

AIM AND OBJECTIVE: Kelch like ECH-associated protein 1 (Keap1) and Nuclear factor-E2 related factor 2 (Nrf2) binding is a key step in the ubiquitination and degradation of Nrf2. The compounds inhibiting this binding exert antioxidant actions. Naturally occurring pentacyclic triterpenoids (PTs) and their synthetic derivatives are projected as activators of Nrf2 signalling. The 16-mer Nrf2 peptide binding site on Keap-1 (PDB: 2 FLU) is proposed to be the prospective target where pentacyclic triterpenoid may exert protein-protein interaction. MATERIAL AND METHOD: In the present study, seventy seven PTs of natural and synthetic origin are screened for Nrf2 stimulatory activity using online PASS (Prediction of Activity Spectrum of Substances) software followed by in silico molecular docking against 16-mer Nrf2 peptide binding site on Keap-1. This virtual screening reveals that Nrf2 stimulatory PTs dock on the 16-mer peptide binding site on Keap-1 and may exert their biological activities by interfering with the Keap-1 and Nrf2 binding. RESULTS: In the present study shows that the small molecules like PT's bind to keap 1 pocket where the 16 mer peptide of Neh2 domain of Nrf2. High docking score of -10.53, -9.08, -8.36, -7.94, -7.49 and -7.18 is shown by glycyrrhizin, asiatic acid, medecassic acid, barrigenic acid, rotundic acid, ursolic acid, respectively. CONCLUSION: The identified hits such as asiatic acid and medecassic acid represent a very promising starting point for the development of potent Nrf2 stimulator. The natural PTs are more promising than the most potent synthetic derivatives of oleanolic acid like CDDO, CDDO-methyl and CDDOimidazol.

Controlled release of therapeutics using interpenetrating polymeric networks.

INTRODUCTION: The ever-increasing developments in pharmaceutical formulations have led to the widespread use of biodegradable polymers in various forms and configurations. In particular, interpenetrating network (IPN) and semi-IPN polymer structures that are capable of releasing drugs in a controlled manner have gained much wider importance in recent years. AREAS COVERED: Recently, IPNs and semi-IPNs have emerged as innovative materials of choice in controlled release (CR) of drugs as the release from these systems depends on pH of the media and temperature in addition to the nature of the system. These networks can be prepared as smart hydrogels following chemical or physical crosslinking methods to show remarkable drug release patterns compared to single polymer systems. EXPERT OPINION: A large number of IPNs and semi-IPNs have been reported in the literature. The present review is focused on the preparation methods and their CR properties with reference to anticancer, anti-asthmatic, antibiotic, anti-inflammatory, anti-tuberculosis and antihypertensive drugs, as majority of these drugs have been reported to be the ideal choices for using IPNs and semi-IPNs.

Design, synthesis and evaluation of small molecule imidazo[2,1-b][1,3,4]thiadiazoles as inhibitors of transforming growth factor-ß type-I receptor kinase (ALK5).

A new series of imidazo[2,1-b][1,3,4]thiadiazoles 5(a-g), 6(a-g), 9(a-i) and 12(a-h) were synthesized as transforming growth factor-ß (TGF-ß) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-ß -induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. Compound 6d, 2-(5-((2-cyclopropyl-6-(4-fluorophenyl) imidazo [2,1-b][1,3,4]thiadiazol-5-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl) acetic acid, shows prominent ALK5 inhibition (IC50 = 0.0012 µM) and elective inhibition (91%) against the P38αkinase at10 µM. The binding mode of compound 6d by XP docking studies shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules.

2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazoles: search for antihyperlipidemic agents.

A novel series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazoles 4(a-d) and 7(a-i) were rationally designed through QSAR based pharmacophore approach and synthesized from 5-(1,3-benzodioxol-5-yl)-[1,3,4]thiadiazol-2-amine (1). The structures of these compounds were established by IR, (1)H NMR, (13)C NMR, HRMS technique. All the compounds were evaluated for their in vitro antihyperlipidemic activity using trition induced hyperlipidemic model. The newly synthesized title compound 7d, 7e and 7h showed a significant decrease in the serum, TCH, TG LDL and VLDL values along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index, LDL:HDL risk ratios and the level of SGOT, SGPT and ALP activities compared to cholesterol induced hyperlipidemic control group.

In vitro anti cancer activity of ethanol extract fractions of Aerva lanata L.

To explore in vitro anticancer potential of Aerva lanata L. (flowering aerial part). The study was performed with 5 different human cell lines for the study of lung, leukaemia, prostate, colon and cervix cancer by using Sulphorhodamine B (SRB) assay. There were three doses of 10, 30 and 100 microg mL(-1) of each Aerva lanata L. Chloroform fraction (ALCF) and Aerva lanata L. Ethyl Acetate Fraction (ALEAF) used in this study. ALCF showed significant % inhibitory effect for leukaemia, lung and colon cancer at maximum concentration of 100 microg mL(-1) as compared to standard drug mitomycin. On the other hand ALEAF showed the significant % inhibitory effect for lung and cervix cancer at maximum concentration of 100 microg mL(-1) as compared to standard drug 5-fluoro Uracil (5-FU). From the above studies it is concluded that, the ethyl acetate fraction and chloroform fraction of Aerva lanata L. provide enough experimental evidence for anticancer activity and these fractions could be useful in medical care.

2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazoles: search for anticancer agents.

In this study, some novel 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles 4 (a-i), 7 (a-p) and 11 (a-i) were synthesized from 5-substituted-1,3,4-thiadiazol-2-amine. The newly synthesized compounds 4a, 4b, 4c, 4e, 4g, 7j, 7l, 11b and 11c were evaluated in the National Cancer Institute for single dose in vitro primary cytotoxicity assay. Among the tested nine compounds, compound 4b (107166/760239) and 4c (107168/760240) were passed the criteria for activity in this assay and scheduled automatically for evaluation against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. 3-(2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)aniline (4c) exhibited significant in vitro anticancer activity against Non Small Cell Lung Cancer HOP-92 cell line (GI(50): 0.114 µM) and Renal Cancer CAKI-1 cell line (GI(50): 0.743 µM).

Benzothiazoles: search for anticancer agents.

Novel derivatives of 2-amino benzothiazoles 4(a-j) have been synthesized and tested for their antitumor activity using National Cancer Institute (NCI) disease oriented antitumor screen protocol against nine panel of cancer cell lines. Among the synthesized compounds, two compounds were granted NSC code and screened at National Cancer Institute (NCI)-USA for anticancer activity at a single high dose (10(-5) M) and five dose in full NCI 60 cell panel. Among the selected compounds, 7-chloro-N-(2,6-dichlorophenyl)benzo[d]thiazol-2-amine (4i) with GI(50) values of 7.18 × 10(-8) M against Non-Small Cell HOP-92 Lung Cancer cell line proved to be the most active members in this study. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors.

A QSAR analysis of 2-phenoxy-N-substituted acetamide analogues as hypoxia-inducible factor-1(HIF-1) inhibitors: a rational approach to anticancer drug design.

A set of thirty one substituted 2-phenoxy-N-phenylacetamide derivatives with HIF-1 inhibitory activities was subjected to 2D and 3D Quantitative Structure Activity Relationship (QSAR) studies using various combinations of descriptors. 2D-QSAR was performed using Multiple Linear Regression (MLR), Principal Component Regression (PCR) and Partial Least Squares Regression (PLS) methods. Among these three methods Multiple Linear Regression (MLR) led to the statistically significant best 2D-QSAR Model-I having correlation coefficient r(2) = 0.9469 and cross validated squared correlation coefficient q(2) = 0.8933 with external predictive ability of pred_r(2) = 0.7128 with the descriptors like SssNHE-index, slogp, T_O_N_1 and T_2_Cl_1. 3D-QSAR study was performed using the simulated annealing variable selection procedures k-nearest neighbor molecular field analysis approach. 3D-QSAR shows interesting results in terms of internal and external predictability. Molecular field analysis was applied for the generation of steric, hydrophobic and electrostatic descriptors based on aligned structures which shows good correlative and predictive capabilities in terms of q(2) = 0.9672 and pred_r(2) = 0.8480. Hence the model proposed in this work provides important structural insight in designing novel derivatives with specific HIF-1 inhibitory activity.

Quantification of Oleanolic acid in the flower of Gentiana olivieri Griseb. by HPLC.

High Performance Liquid Chromatography (HPLC) method is a potent analytical technique for determining phytoconstituents even in minute quantities particularly that are generally present in traces concentrations in medicinal plants. The concentration of oleanolic acid (OA) in the Gentiana olivieri Griseb.(GOG) flowers is quantitatively determined by a simple, precise and accurate HPLC method. HPLC assay was performed on reversed-phase C18 column and compound was detected at 210 nm with a flow rate of 1.0 ml/min. The mobile phase consisted of methanol (A) and 0.03 mol/L phosphate buffer, pH 2.9 (B) with a ratio of 85:15 (A: B v/v).The method showed good precision and accuracy with overall intra-day and inter-day variation of 0.36-1.33% and 0.43-1.15%, respectively, and overall recoveries of 99.32%. Application of these methods to determine the OA in Gentiana olivieri Griseb showed that the concentration of OA was found more in the flower as compared to the whole aerial part (average amount in flower 1.82 mg/g DW and 0.75 mg/g DW in whole aerial plant). A simple and accurate HPLC method has been developed for quantitative determination of OA in GOG flowers.

Immunomodulatory activity of butanol fraction of Gentiana olivieri Griseb. on Balb/C mice.

OBJECTIVE: To explore the immunomodulatory properties of 80% ethanol extract and butanol fraction of Gentiana olivieri (G. olivieri) Griseb on Balb/C mice. METHODS: The study was performed with basic models of immunomodulation such as the humoral antibody response (hemoglutination antibody titres), cell mediated immune response (delayed type hypersensitivity and in vivo carbon clearance or phagocytosis). Ethanol (80%) extract of flowering aerial parts of G. olivieri and its butanol fraction were administered p.o. (orally) to the mice. Levamisole, 2.5 mg/kg was used as standard drug. RESULTS: There was a potentiation of immune response to sheep red blood cells by cellular and humoral mediated mechanisms comparable to levamisole (2.5 mg/kg) by both 80% ethanol extract and the butanol fraction at doses of 50-200 mg/kg in male Balb/C mice. Both significantly (P<0.01) potentiated the humoral immune response in cyclophosphamide (250 mg/kg) immunosupressed mice at 100 and 200 mg/kg of each extract and fraction as compared to control. The potentiation of delayed type hypersensitivity response was statistically significant (P<0.01) at 200 mg/kg of ethanol extract and 100, 200 mg/kg of butanol fraction as compared to control. The phagocytosis was significant at 200 mg/kg with butanol fraction of G. olivieri. CONCLUSIONS: The results reveal the immunostimulant effects of plant G. olivieri in mice by acting through cellular and humoral immunity in experimental models of immunity in mice. Butanol fraction is the most effective at a dose level of 200 mg/kg.

Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b][1,3,4]-thiadiazole derivatives.

A series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]-thiadiazole derivatives 4(a-k) have been prepared by reaction of 2-amino-5-cyclopropyl-1,3,4-thiadiazole and an appropriate phenacyl bromide. Further 5-bromo 5(a-k) and 5-thiocyanato 6(a-k) derivatives were synthesized in order to study the effect of these substituents on antitumor activity. Structures of these compounds were established by IR, (1)H NMR, (13)C NMR and Mass spectroscopy. Seven compounds were granted NSC code at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the compounds tested, 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazole 5b (NSC D-96022/1) was found to be the most active candidate of the series at five dose level screening with degree of selectivity toward Leukemic cancer cell line.

A comparative QSAR analysis of quinazoline analogues as tyrosine kinase (erbB-2) inhibitors.

In this paper, an attempt was made to develop a Quantitative Structure Activity Relationship (QSAR) model on a series of quinazoline derivatives acting as Protein tyrosine kinases (erbB-2) inhibitors using Multiple Linear Regression, Principal Component Regression and Partial Least Squares Regression methods. Among these three methods, Multiple Linear Regression (MLR) method has come out with a very promising result as compared to other two methods. Various 2D descriptors were calculated and used in the present analysis. For model validation, the dataset was divided into training and test sets using spherical exclusion method. The developed MLR- QSAR model was found to be statistically significant with respect to training (r2 =0.956), cross-validation (q2 = 0.915), and external validation (pred_r2= 0.6170). The developed MLR model suggests that Estate Contribution descriptors SaaOE-Index (30.07%) and SsCIE-index (15.79%) are the most important descriptors in predicting Tyrosine kinase (erbB-2) inhibitory activity. Electron withdrawing group at 4th position of quinazoline enhances the activity as evident by positive value of SsClE-index (15.79). In addition, for quinazoline substituents, estate contribution descriptors SsCH3E -index has a large deactivating effect.

Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: search for anticancer agent.

The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Among the synthesize compounds, seventeen compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the selected compounds, 3-(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI50 1.82 & 2.14 µM respectively. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives.

Synthesis and antimicrobial activity of 7-(2-substituted phenylthiazolidinyl)-benzopyran-2-one derivatives.

A series of 7-(2-substituted phenylthiazolidinyl)-benzopyran-2-one derivatives have been synthesized by reaction of 7-amino-4-methyl-benzopyran-2-one (1) with an appropriate substituted aldehydes to obtain various Schiff bases (3a-k) which on treatment with thioglycolic acid afforded the title compounds (4a-k). Purity of the compounds has been confirmed by TLC. Structure of these compounds were established on the bases IR, 1H NMR, 13C NMR and Mass spectral data. Schiff bases and title compounds were evaluated for antibacterial and antifungal activities against various bacterial and fungal strains. The results showed that compounds 3d, 3f, 4d, 4f and 4i (100 microg/ml) exhibited good antibacterial and antifungal activity as that of standard antibiotics Ciprofloxacin and Griseofulvin.

3d QSAR studies on a series of quinazoline derrivatives as tyrosine kinase (egfr) inhibitor: the k-nearest neighbor molecular field analysis approach.

Epidermal growth factor receptor (EGFR) protein tyrosine kinases (PTKs) are known for its role in cancer. Quinazoline have been reported to be the molecules of interest, with potent anticancer activity and they act by binding to ATP site of protein kinases. ATP binding site of protein kinases provides an extensive opportunity to design newer analogs. With this background, we report an attempt to discern the structural and physicochemical requirements for inhibition of EGFR tyrosine kinase. The k-Nearest Neighbor Molecular Field Analysis (kNN-MFA), a three dimensional quantitative structure activity relationship (3D- QSAR) method has been used in the present case to study the correlation between the molecular properties and the tyrosine kinase (EGFR) inhibitory activities on a series of quinazoline derivatives. kNNMFA calculations for both electrostatic and steric field were carried out. The master grid maps derived from the best model has been used to display the contribution of electrostatic potential and steric field. The statistical results showed significant correlation coefficient r(2) (q(2)) of 0.846, r(2) for external test set (pred_r2) 0.8029, coefficient of correlation of predicted data set (pred_r(2)se) of 0.6658, degree of freedom 89 and k nearest neighbor of 2. Therefore, this study not only casts light on binding mechanism between EGFR and its inhibitors, but also provides hints for the design of new EGFR inhibitors with observable structural diversity.