Structure activity relationship studies of cinnamic acid derivatives as inhibitors of human neutrophil elastase revealed by ligand docking calculations

Structure-activity relationship of cinnamic acid derivatives as inhibitors of the human neutrophil elastase is reported. Comparison of the inhibitory concentrations (IC50 values) with the results of the ligand docking calculations revealed that the structure element of the aromatic ortho-dihydroxy groups combined with a lipophilic residue seems to be a prerequisite for an optimal binding within the active site.     

3D-QSAR and docking studies of piperidine carboxamide derivatives as ALK inhibitors

Anaplastic lymphoma kinase (ALK) is an important and attractive target for the design of new anticancer drugs. In the present study, quantitative structure–activity relationship (QSAR) models of piperidine carboxamide derivatives against ALK were developed by CoMFA and CoMSIA approaches. Both the CoMFA and CoMSIA models yielded significant statistical results. The results of the QSAR model indicated the importance of steric, electrostatic, and hydrophobic properties in the potent ALK inhibitors. Furthermore, molecular docking of the most active compound 25 with the active site of ALK was also investigated. The outcomes of this study may result in a better understanding of the inhibition mechanism of ALK and aided in the development of new and more potent anticancer drugs.     

Quantitative evaluation of isothiocyanates as substrates and inhibitors of P-glycoprotein

The ATP-binding cassette transporter P-glycoprotein (P-gp) exerts a critical role in the systemic disposition of, and exposure to, lipophilic and amphipathic drugs, carcinogens, toxins and other xenobiotics. The ability of P-gp to transfer a wide variety of structurally unrelated compounds from the cell interior across the membrane bilayer remains intriguing. Since dietary chemicals in cruciferous and several other foods appear to exert anticarcinogenic effects by inducing phase II enzymes and inhibiting some phase I enzymes, the isothiocyanate constituents are frequently studied for interactions with various biomacromolecules as well as cytotoxins or isolated cells. Several prominent dietary isothiocyanates were characterized for their interaction with P-gp and their specific effects on the P-gp export activity of several marker substrates. Some of these compounds inhibit the active P-gp-mediated efflux of the fluorescent markers LDS-751 and daunorubicin with low potency, with the most potent among them, phenethyl isothiocyanate, inhibiting transport of the LDS-751 substrate with an IC(50) of approximately 240 microM. Overall, these isothiocyanates are unlikely to impede the xenobiotic defence function of P-gp even in the intestine where the concentrations are potentially high.     

Quantitative structure activity relationship (QSAR) studies of a series of 2,5-disubstituted-1,3,4-oxadiazole derivatives as biologically potential compounds

2,5-disubstituted-1,3,4-oxadiazoles and its derivatives are reported to possess wide spectrum of biological activities ranging from antibacterial, antiviral, anti-Parkinson, anti-HIV, and anti-inflammatory activity. Quantitative structure activity relationship (QSAR) analysis is generally carried out to study quantitative relationship between the physicochemical parameters and the biological activity. In the present study, QSAR studies for a set of some disubstituted-1,3,4-oxadiazole derivatives were conducted using TSAR 3.3 software. The in vitro antibacterial activity (MICs) of the compounds against S. aureus and E. coli exhibited good correlation (n = 36, r ² > 0.7, r _cv² > 0.5, s = 0.069) with the prediction made by the model. It was found that the polarizability, thermodynamic, and lipophilicity were major responsible factors for exhibiting the activity.     

Molecular docking and 3D-QSAR studies of 2-substituted 1-indanone derivatives as acetylcholinesterase inhibitors

Aim： To explore the binding mode of 2-substituted 1-indanone derivatives with acetylcholinesterase （ACHE） and provide hints for the future design of new de- rivatives with higher potency and specificity. Methods： The GOLD-docking con- formations of the compounds in the active site of the enzyme were used in subse- quent studies. The highly reliable and predictive three-dimensional quantitative structure-activity relationship （3D-QSAR） models were achieved by comparative molecular field analysis （CoMFA） and comparative molecular similarity analysis （CoMSIA） methods. The predictive capabilities of the models were validated by an external test set. Moreover, the stabilities of the 3D-QSAR models were veri- fied by the leave-4-out cross-validation method. Results： The CoMFA and CoMSIA models were constructed successfully with a good cross-validated coef- ficient （q2） and a non-cross-validated coefficient （r2）. The q2 and r2 obtained from the leave- 1-out cross validation method were 0.784 and 0.974 in the CoMFA model and 0.736 and 0.947 in the CoMSIA model, respectively. The coefficient isocontour maps obtained from these models were compatible with the geometrical and physi- cochemical properties of ACHE. Conclusion： The contour map demonstrated that the binding affinity could be enhanced when the small protonated nitrogen moi- ety was replaced by a more hydrophobic and bulky group with a highly partial positive charge. The present study provides a better understanding of the inter- action between the inhibitors and ACHE, which is helpful for the discovery of new compounds with more potency and selective activity.     

Synthesis,biological screening and molecular docking studies of novel 4,6-pyrimidine derivatives as EGFR-TK inhibitors

Novel 4, 6-disubstituted pyrimidine derivatives (5–16) were synthesized in four steps starting from 2,4-dichloropyrimidine and screened for their cytotoxicity using brine shrimp (Artemia Salina) lethality bioassay. The compounds such as 6, 11, 14 and 15 were found to be more toxic. The compounds were also studied for in vitro anticancer properties using six different cancer cell lines viz SIHA, PANC-1, MDA-MB-231, IMR-32, DU145 and A549. The compound 14 was effective inhibitor of SIHA and DU145, whereas compound 16 in Panc 1 and A549, compound 7 in MDA-MB-231 and compound 6 in IMR 32 respectively. Molecular docking studies were carried out using an X-ray crystallographic structure of epidermal growth factor receptor tyrosine kinase to explore the possible mode of action of compounds as epidermal growth factor receptor tyrosine kinase inhibitors.     

3D-QSAR and docking studies of benzoyl urea derivatives as tubulin-binding agents for antiproliferative activity

Tubulins, an αβ heterodimers, the major component of microtubules, are important molecular target of numerous small molecule ligands for anticancer therapy. In this study, the molecular modeling studies were performed to develop predictive 3D-QSAR models using set of 32 compounds of benzoyl urea derivatives as tubulin-binding agents for antiproliferative activity. A five-point common pharmacophore hypotheses with one hydrogen bond acceptor (A), two hydrogen bond donors (D), one hydrophobic (H), and one ring (R) vector features were selected for alignment of all compounds. The 3D-QSAR models generated using training set of 21 compounds and test set of 11 compounds showed good partial least squares statistical results. The developed CPHs and 3D-QSAR models were validated further externally by predicting the activity of database of compounds from literature and comparing it with actual activity. Docking studies were also carried out for all compounds on colchicine-binding site of β-tubulin for studying of binding affinity of compounds for antiproliferative activity. The results of these molecular modeling studies are helpful to refine the pharmacophore for design of new potential compounds for antiproliferative activity.     

Betulinic acid derivatives as anticancer agents: structure activity relationship

Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.     

Synthesis, antimicrobial evaluation, and docking studies of novel 4-substituted quinazoline derivatives as DNA-gyrase inhibitors

Quinazoline derivatives are reported to have anti‐inflammatory, analgesic, antibacterial, and anticancer activities. The incorporation of “OCH₂CONH₂” (oxymethylcarbamide) at 4^th position of the quinazoline ring was found to influence the biological activities of the molecules. With this rationale, some new oxadiazolyl methyloxy quinazolines, pyrazolyl acetoxy methyl quinazolines, triazolylmethyloxy quinazolines were synthesized from anthranilic acid through quinazolyl oxyacetylhydrazide intermediates. All the compounds were characterized by IR, ¹H‐NMR, EI‐MS, and C, H, N analyses and evaluated for their antimicrobial activity. Docking studies on the DNA‐gyrase enzyme (1KZN) show their role in the antimicrobial activity of the molecules and explain the higher potency of compounds 6a , 6b , 8a , 8b based on ReRanking scores and binding poses of the molecules.     

3D QSAR CoMFA/CoMSIA and docking studies on azole dione derivatives, as anti-cancer inhibitors

Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were performed on a series of 103 azole dione derivatives, as selective anti-cancer inhibitors. The atom and shape based root mean square alignment yielded the best predictive CoMFA model q2 = 0.923, r2 = 0.980, when compared with the CoMSIA model. Docking studies were employed to position the inhibitors into active site of Crystal Structure of Delta (4)-3-ketosteroid 5-beta-reductase (PDB id: 3BUR). Results that indicate steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor substituents play a significant role in design novel, potent and selective anti-cancer activity of the compounds.     

3D-QSAR and docking studies on pyridopyrazinones as BRAF inhibitors

BRAF has become an important and exciting therapeutic target toward human cancer. 3D-QSAR and docking studies were performed to explore the interaction of the BRAF with a series of pyridopyrazinones. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were carried out in terms of their potential for predictability. The CoMFA and CoMSIA models using 71 compounds in the training set gave r _cv² values of 0.567 and 0.662, r ² values of 0.900 and 0.907, respectively. The 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained by 3D-QSAR models may be useful to design novel potential BRAF inhibitors.     

Quantitative structure–activity relationship studies of cyclooxygenase inhibitors: a comprehensive analysis

A quantitative structure‐activity relationship (QSAR) analysis of 10 structurally diverse set of compounds recently reported as cyclooxygenase (COX) inhibitors has been performed using ClogP, CMR, aromatic substituent constants, and suitable indicator variables. These revealed several important physicochemical and structural requirements for COX‐1, COX‐2 inhibitory activity, and selective inhibition of COX‐2 versus COX‐1 among these novel ligands. Seventeen QSAR models reported herein provide interesting insights in understanding the hydrophobic, steric, electronic, and structural requirements of COX inhibition among these individual set of compounds. These results may be used to further the design and development of selective COX‐2 inhibitors among these newly reported COX inhibitors. Drug Dev Res 64:220–231, 2005. © 2005 Wiley‐Liss, Inc.     

Quantitative structure-activity relationship studies of non-aromatic analogues of ethanolamine as inhibitors of phenylethanolamine N-methyltransferase

The phenylethanolamine N-methyltransferase inhibition potency of non-aromatic ethanolamines is found by regression analysis to be significantly correlated with van der Waals volume, Vw. For the proper inhibition of this enzyme the size of a substituent on beta-carbon of ethanolamine chain should be comparable to the cavity size of enzyme and there should be no other bigger group present on this carbon, which can cause a steric crowding, when the molecule approaches the reactive site of the enzyme.