Current Issue : July-September Volume : 2018 Issue Number : 3 Articles : 18 Articles
The current investigation involved Maestro 9.1 software assisted in-silico molecular docking based exploration of 5-lipoxygenase (PDB ID: 1N8Q) inhibitory potentials of some 10,13-dimethyl-6-methylheptan-2-yl)-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) derivatives; (R,3E,7E)-((3R,10R,13R,14R)-10,13-dimethyl-17-((S)-6-methylheptan-2-yl)-2,3,4,7, 8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) -5-hydroxy-3-methyl-9-methyleneundeca-3,7-dienoate (1), (E)-((3R,10R,13R,14R)-10,13-dimethyl-17-((S)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro -1H-cyclopenta[a]phenanthren-3-yl)-6-oxooct-4-enoate (2) and (S)-1-((3R,10R,13R,14R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) -5-methyl-3-((R,E)-1-amino-3-ethyl-6-oxohept-3-enyl)pentanedioate (3) which will have enormous significance in suppressing inflammatory responses. All the inhibitors (1-3) exhibited excellent interaction with the target, displaying impressive Glide scores of -8.59 Kcal/mol, -8.41 Kcal/mol and -9.47 Kcal/mol. The Van der Waals contacts of the inhibitors were found to be 819 (1), 1263 (2) and 1543 (3), respectively. The best binding was displayed by inhibitor 3, by the amine moiety which strongly binds with the amino acid residues Gln609 and Leu607. The carbonyl oxygen interacted with Arg596 (1), Gln557 (2) and Asn180 (3), respectively. The study demonstrated a significant interaction of the 10,13-dimethyl-6-methylheptan-2-yl)-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) derivatives, as revealed by high Glide Score against lipoxygenase, by the virtue of oxygen and nitrogen atoms present in the scaffold which made hydrogen bonds with the active site amino acid residues. This may be translated as a leading approach of suppressing inflammatory responses and symptoms. Therefore, the study will enlighten the path for medicinal chemists while designing specific inhibitors based on this scaffold against any molecular target....
5-LOX is predominantly involved in the inflammatory and allergic reactions as it facilitates the synthesis of the more potent inflammatory mediator; leukotrienes (LTs). In several human ailments like psoriasis, asthma, rheumatoid arthritis, colitis ulcerosa and allergic rhinitis, a very high level of LTs have been observed. The best way of reducing the inflammation is the complete termination of LT production which can be achieved directly or indirectly by the inhibition of the lipoxygenase pathway. The current research emphasis on anti-inflammatory screening of two molecules; 5,5-dimethyl-decahydro-5H-benzo[h]naphtho[1,2-c]chromene scaffold; (6aS,6bR,8aR,10R,12bR)-10,14-dihydroxy-5,5-dimethyl-6,6a,6b,7,8,8a,9,10,11,12b-decahydro-5H-benzo[h]naphtho[1,2-c]chromene-8a-carbaldehyde (1) and (6aR,6bS,8aR,10R,12bR,14aR)-8a-acetyl-10-hydroxy-5,5-dimethyl-6,6a,7,8,8a,9,10,11,12b,14a-decahydro-5H-benzo[h]naphtho[1,2-c]chromen-14(6bH)-one (2) as the 5-LOX inhibitor by utilizing the Maestro 9.1 software mediated induced-fit molecular docking method. The current research represented a molecular docking study which helped in revealing the essential structural features for modulating LOX. In the ligand 1, the obtained Glide Score was found to be -9.67 Kcal/mol whereas the ligand 2 expressed higher Glide Score of -10.95 Kcal/mol. From this study, a number of postulations may be expressed related to the essential structural requirements. First, a hydroxyl group attached to the chromene scaffold is essential for interacting with the active site of LOX. Secondly, it may be believed that stereochemistry has a thoughtful role in mediating inflammatory mediator suppression. Therefore, this study will definitely motivate the researchers across the world in further exploring the 5,5-dimethyl-decahydro-5H-benzo[h]naphtho[1,2-c]chromene scaffold for modulating a large number of biological targets by rationally designing optimized, better, and potent inhibitors....
Inflammation is a protective mechanism of the human body and is an imperative essential process for the existence of life. However, enhanced inflammatory responses often precipitate unwanted chemical reactions which ultimately results in the aggravation of disease conditions like arthritis, bronchial asthma, inflammatory bowel disease (IBD), etc. The current research involved a Maestro 9.1 software (Glide module) assisted molecular docking study of two pyran non steroidal anti-inflammatory candidates (NSAIC); 2-(but-3-en-1-yl)-5-nonyltetrahydro-2H-pyran (1) and 5-(7-butoxydodecyl)-2-(2-ethylbut-3-en-1-yl)-3,6-dihydro-2H-pyran (2) against anti-inflammatory target 5-LOX (PDB ID: 1N8Q) to determine the potential of experimental molecules. Both the structures had exactly the same Glide score of -5.47 Kcal/mol. It was found that both the compounds 1 and 2 binds perfectly by forming hydrogen bonding with the polar amino acid residues; Gln 514 and Asn 554. The Van der Waals contacts of structure 1 and 2 were found to be 1603 and 1736, respectively, which represented high structural stability to the protein-ligand complex. The structure 1 formed hydrogen bonding with the oxygen atom present in the pyran ring whereas the structure 2 made hydrogen bonding with the oxygen atom present in the chain and the water molecule present in the protein. The studies have also shown that the inhibitors bind firmly to the open cavity and may thus prevent the access of the substrate to the catalytic site of 5-LOX....
Inflammation is a major vital biochemical process which has its own importance. The modern therapeutics have seen several complications in long-term usage. Therefore, very recently, a great pace has been observed in the area of rational drug discovery of novel non-steroidal anti-inflammatory candidates (NSAIC), where the pharmacological potentials of the multiple fused rings (4 to 5 rings) need to explore and further optimize them by rational approaches. The present study involved Glide module of Maestro 9.1 software mediated molecular docking of some 2,9,9-trimethyl-10-(2-phenylacetoxy)-icosahydropicene-2-carboxylate derivatives; namely, (1R,2R,4aR,6aR,6bR,8aR,10R,12aR,12bR,14aR,14bR)-methyl-1-hydroxy-2,9,9-trimethyl-10-(2-phenylacetoxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,14a,14b-icosahydropicene-2-carboxylate (inhibitor A) and (1R,2R,4aR,6aR,6bS,8aR,10R,12S,12aR,12bS,14aR)- methyl-1,12-dihydroxy-2,9,9-trimethyl- 10-(2-phenylacetoxy)-1,2,3,4,4a,5,6, 6a,6b,7,8,8a,9,10,11,12,12a,12b,14a,14b-icosahydropicene-2-carboxylate (inhibitor B) as NSAIC by inhibiting inflammatory mediator COX-2. Both the molecules formed stable hydrogen bonds where the initial (inhibitor A) formed bonding with the Thr181 residue via =O (carbonyl) moiety with Glide score of -10.02 kcal/mol, whereas the later (inhibitor B) formed hydrogen bonding with the Tyr324 via the ââ?¬â??OH (hydroxyl) moiety with Glide score of -7.46 kcal/mol. From the above results, it can be concluded that these classes of compounds may have perspectives to be emerging anti-inflammatory candidates for treating a variety of ailments related with inflammation with pronounced activity, reduced toxicity and cost-effectiveness....
In the previous studies, the role of two molecules of 5,5-dimethyl-decahydro-5H-benzo[h]naphtho[1,2-c]chromene; (6aS,6bR,8aR,10R,12bR)- 10,14-dihydroxy-5,5-dimethyl-6,6a,6b,7,8,8a,9,10,11,12b-decahydro -5H-benzo[h] naphtho[1,2-c] chromene-8a-carbaldehyde (1) and (6aR,6bS,8aR,10R,12bR,14aR)-8a-acetyl-10-hydroxy-5,5-dimethyl-6,6a,7,8,8a,9,10,11,12b, 14a-decahydro-5H-benzo[h]naphtho[1,2-c]chromen-14(6bH)-one (2) as anti-inflammatory agent was established by in-silico studies where through induced-fit molecular docking method, the inhibitory potentials against cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) were screened. In the present research, the essential pharmacokinetic properties (as well as toxicity aspects) of the compounds were predicted using the QikProp module of Maestro 9.1 software to determine whether the proposed molecules will have enough perspective to present the intended drug action with no compromise in the bioavailability along with the probable toxicity profile. The current research revealed several imperative pharmacokinetics cum toxicity profiles of two 5,5-dimethyl-decahydro-5H-benzo[h]naphtho[1,2-c]chromene derivatives. The compounds were found to follow the Lipinski Rule of 5 and Jorgensen Rule of 3. A remarkable oral absorption of 100% was predicted for both the molecules. However, maximal transdermal transport rate and skin permeability values were observed to be quite low and the alternative route of transport was seen to be insignificant. Apparent Caco-2 predicted values were monitored to be > 500 for both the molecules which signified better human intestinal absorption. The molecules were detected to be less prone to cardiac toxicity. The serum protein binding was found to be quite considerable where major fractions of the compounds are likely to circulate freely. Thus, the present work will provide adequate data in rationally designing the novel chromene based hybrid molecules having better pharmacokinetics and toxicity profiles....
Inflammation is an important process in the human body which is broadly mediated by two main enzymes; cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). The heterocyclic compounds are the most emerging class of anti-inflammatory agents. The present investigation aimed at exploring of anti-inflammatory perspective through molecular docking study on cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) of (5aR)-8-ethyl-6-vinyl-3,3a,5a,6-tetrahydroazuleno[1,8-cd]pyran-1,4(5H,9H)-dione, a fused pyran based compound having an aromatic part and a five-member component, utilizing Glide module of Maestro 9.1 software. A brilliant binding of the ligand with the macromolecule was observed by the IFD binding scores. The molecule exhibited interaction with COX-2 via formation of stable hydrogen bonding through Tyr324 with the = O (carbonyl) moiety present in the five-membered portion, demonstrating Glide score of -8.86 kcal/mol. In contrast, the molecule displayed interaction with the 5-LOX via formation of stable hydrogen bonding through Gln514 with =O (carbonyl) moiety present in the pyran part, demonstrating Glide score of -8.22 kcal/mol. From the examined data, a conclusive fact can be articulated about its future perspectives in clinical utility as a promising candidate for the treatment of ailments of multiple origins. The study will definitely inspire medicinal chemists in developing new generations of anti-inflammatory pyrans....
Various inflammatory mediators implicated in the pathological process include prostaglandins (PG), thromboxanes and leukotrienes. The production of various PG is directed by the coordinated activity of eicosanoid forming enzymes named cyclooxygenase (COX). However, they are not devoid of gastrointestinal effects entirely and their use (like all NSAIDs) has been associated with a higher risk of stroke and heart attack. The present research is a maiden attempt to explore the anti-inflammatory potential of some unexplored decahydrophenanthren-one derivatives with a belief of developing potent compounds with reduced associated side-effects. Here, the two molecules; (4bS,7S,8aS)-1,1,4b-trimethyl-7-vinyl-1,4b,5,6,7,8,8a,9,10,10a-decahydrophenanthren-3(2H)-one (1) and (2R,4aR,7R,10aS)-7-hydroxy-2-vinyl-2,3,4a,4b,5,6,7,8,10, 10a-decahydrophenanthren-4(1H)-one (2) were screened for their COX-2 inhibitory perspectives as future anti-inflammatory agent by using induced-fit molecular docking technique against PDB crystal structure (PDB ID: 3LN1) by employing Maestro 9.1 software. The IFD studies highlighted the potentials of both the ligands in exhibiting interaction with the amino acid residues present at the active site of the inflammatory mediator COX-2, thereby facilitating the anti-inflammatory activity. The ligand 1 displayed demonstrated highest Glide Score of -8.67 Kcal/mol, followed by ligand 2 with Glide Score of -7.02 Kcal/mol. This docking study of theses future NSAIDs revealed the imperative structure necessities for the modulation of the biological activity. Based on the promising anti-inflammatory effect, these low-molecular-weight ligands of decahydrophenanthren-one scaffold will definitely inspire the modern era researchers in developing better and more potent, optimized analogs for overcoming the present limitations....
Diabetes, a chronic disease occurs when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. The current therapeutic agents for type-2 diabetes are associated with some side effects like sudden hypoglycemia, weight loss etc. The global prevalence of diabetes is estimated to be 9% among adults. DPP-4 inhibitors are a new class of oral hypoglycemics that block DPP-4 enzyme and are used to treat diabetes mellitus type-21. DPP-4 inhibitors like sitagliptin has relatively less side effects, hence in present study 32 compounds containing benzofuran ring were designed and their interaction with DPP-4 enzyme studied using Schrodinger small molecule drug discovery suite (Maestro 10.3)....
On thorough literature search, it was found that this scaffold was never utilized for any exploration towards anti-inflammation studies. Therefore, the cyclooxygenase-2 (COX-2) (the most prominent enzyme responsible for aggravating inflammation) inhibitory potential of a few well-known compounds of cyclopenta[a]phenanthrene scaffold were in-silico studied. The present study involved exploration of anti-inflammatory potentials of some of the 10,13-dimethyl-6-methylheptan-2-yl)-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) derivatives; (R,3E,7E)-((3R,10R,13R,14R)-10,13-dimethyl-17-((S)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) -5-hydroxy-3-methyl-9-methyleneundeca-3,7-dienoate (1), (E)-((3R,10R,13R,14R)-10,13-dimethyl-17-((S)-6-methylheptan-2-yl)-2,3,4,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-6-oxooct-4-enoate (2) and (S)-1-((3R,10R,13R,14R) -10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a] phenanthren -3-yl)-5-methyl-3-((R,E)-1-amino-3-ethyl-6-oxohept-3-enyl)pentanedioate (3) by molecular docking technique utilizing the Glide module of Maestro 9.1 software using the celecoxib bound PDB file of COX-2 (PDB ID: 3LN1). All the three derivatives have a higher perspective of acting as potent COX-2 inhibitor as revealed by high Glide Score. The IFD results showed that inhibitor 1 had the highest Glide score of -9.13 Kcal/mol compared to other inhibitors. The good binding affinity of this inhibitor may be due to the various interactions such as hydrogen bonding, interactions of hydrophobic, hydrophilic, electrostatic and steric origin. The compound significantly demonstrated hydrogen bonding with four amino acid residues of the active site; His183, Gln423, Asn351 and Thr181. This study opened several avenues of research, betterment and future directions of upbringing the scaffold based inhibitors in the near future....
The present exploration is a molecular docking study of some 2,9,9-trimethyl-10-(2-phenylacetoxy)-icosahydropicene-2-carboxylate derivatives; namely, (1R,2R,4aR,6aR,6bR,8aR,10R,12aR,12bR,14aR,14bR)-methyl-1-hydroxy-2,9,9-trimethyl- 10- (2-phenylacetoxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,14a,14b-icosahydropicene-2-carboxylate (1) and (1R,2R,4aR,6aR,6bS,8aR,10R,12S,12aR,12bS,14aR)-methyl-1,12-dihydroxy-2,9,9-trimethyl-10-(2-phenylacetoxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,14a,14b-icosahydropicene-2-carboxylate (2) against the inflammatory mediator 5-LOX by utilizing the Glide module of Maestro 9.1 software. The ligand 1 displayed a very strong binding with 5-LOX, demonstrating Glide score of -10.32 Kcal/mol, owing to the formation of four hydrogen bonding through the carbonyl (=O), hydroxyl (-OH) and oxo (-O-) groups present in the pharmacophore with the amino acid residues; Ala672, Asn554, Leu607 and Gln363. The compound 2 expressed limited binding with receptor residues; Phe177 and Gln413 through the hydroxyl group present, showing a Glide score of -7.46 Kcal/mol. The molecular docking of the derivatives demonstrated specific binding with the target 5-LOX which may exhibit as anti-inflammatory activity. The study highlights the importance of specific groups and their position in the pharmacophore which enabled better interaction with the target residues. The stereochemistry also played an immense role in the binding with the inflammatory mediator. From both the structures of this pharmacophore, a conclusion may be drawn regarding the optimized structure which will strongly bind via hydrogen bonding. However, more studies and rational design are universally needed for the practical development of these therapeutic inhibitors. The study will revolutionize the importance of icosahydropicene-2-carboxylate based inhibitors in the treatment of inflammatory conditions....
Non-steroidal anti-inflammatory drugs (NSAIDs) block the COX enzymes and reduce production of prostaglandins. Therefore, inflammation, pain and fever are reduced by all COX inhibitors. However, the COX-2 inhibitors may increase the risk of serious, even fatal, stomach and intestinal adverse reactions such as bleeding, ulcers and perforation of the stomach or intestines. To overcome these side-effects, the best strategy was to explore the pharmacological perspectives of novel class groups. In the present research, two molecules of 5,5-dimethyl-decahydro-5H-benzo[h]naphtho[1,2-c]chromene; (6aS,6bR, 8aR,10R,12bR)- 10,14-dihydroxy-5,5-dimethyl- 6,6a,6b,7,8,8a,9,10,11,12b-decahydro-5H-benzo[h]naphtho[1,2-c] chromene-8a-carbaldehyde (1) and (6aR,6bS,8aR,10R,12bR,14aR)-8a-acetyl-10-hydroxy-5,5-dimethyl-6,6a,7,8,8a,9,10,11,12b,14a-decahydro-5H-benzo[h]naphtho[1,2-c]chromen-14(6bH)-one (2) were screened for anti-inflammatory agent as the COX-2 inhibitor using PDB crystal structure (PDB ID: 3LN1) employing induced-fit molecular docking method utilizing the Maestro 9.1 software. The molecular docking studies revealed that both the ligands of 5,5-dimethyl-decahydro-5H-benzo[h]naphtho[1,2-c]chromene derivatives scaffold expressed noteworthy anti-inflammatory activity as the ligands bound strongly with the inflammatory mediator COX-2. Both the ligands displayed formation of 5 strong hydrogen bonding with the amino acid residues (Asn351, His183 and Thr181) of the biological target. Ligand 1 demonstrated the highest Dock Score of -9.75 Kcal/mol. From the obtained IFD data, it can be concluded that the ligands of this scaffold are the emerging and promising candidates for treating inflammatory responses in clinical practices. The research will inspire the scientists across the globe in developing more potent and better analogs of this scaffold for treating inflammatory conditions....
Heterocyclic compounds have emerged as potent medicinal agents in the 21st century. In the market, nearly 75% of the modern drugs are of heterocyclic origin. Pyran or oxine are the six-membered non-aromatic heterocyclic compound known for exhibiting multifarious pharmacological activities. The existing exploration involved discovering the ability of two 2-substituted pyran molecules; (R)-2-(but-3-enyl)-tetrahydro-2H-pyran (1) and (R)-2-((S)-2-ethylbut-3-enyl)-3,6-dihydro-2H-pyran (2) in inhibiting anti-inflammatory target activity cyclooxygenase-2 (COX-2) by molecular docking study utilizing Glide module of Maestro 9.1 software. In an addition, the ADME studies were carried out to establish the significant parameters like toxicity, profiling of pharmacokinetic parameters and ability to administer by the oral route. The applied molecular docking studies helped to explore the interaction of the 2-substituted pyrans compounds with the anti-inflammatory target COX-2 where a stable binding was observed with the polar glycine residues. The QikProp assisted prediction of ADME of the 2-substituted pyran compounds has shown to follow the Lipinski’s rule of five and is completely non-toxic. Overall, both the compounds have desired pharmacokinetic profile which emphasizes better druggability. Therefore, it may be concluded that the pyran ring of both structures instigated the interaction by the formation of hydrogen bonds. It necessitates that the pyran ring plays a crucial role in the COX-2 enzyme inhibition....
5-LOX play a pivotal role in the synthesis of leukotrienes (LTs) which is a potent inflammatory mediator. The strategies for the control of inflammatory responses involved inhibition of the 5-LOX which will directly inhibit the LTs production, thereby resulting in complete management of disease like asthma, allergic rhinitis, psoriasis, rheumatoid arthritis and colitis ulcerosa. The existing interesting study represents a committed effort for investigating the 5-LOX inhibitory potential (PDB ID: 1N8Q) by in-silico induced-fit molecular docking techniques employing Maestro 9.1 software for two low-molecular-weight ligands of decahydrophenanthren-one scaffold; (4bS,7S,8aS)-1,1,4b-trimethyl-7-vinyl-1,4b,5,6,7,8,8a,9,10,10a-decahydrophenanthren-3(2H)-one (1) and (2R,4aR,7R,10aS)-7-hydroxy-2-vinyl-2,3,4a,4b,5,6,7,8,10,10a-decahydrophenanthren -4(1H)-one (2). The present study represented an attempt of developing future NSAIDs of decahydrophenanthren-one scaffold with LMWL perspective which will have the capability to inhibit the essential inflammatory mediators. The ligand 1 exhibited Glide Score of -10.01 Kcal/mol by interacting with the Ile857 residue of the active site of 5-LOX. The ligand 2 expressed better Glide Score of -10.70 Kcal/mol by interacting with the active site amino acid residue Gln716. From the study, it was recognized that the position of the substituents and their type is crucial in inhibiting the target. The position of the carbonyl on the third ring and the hydroxyl group in the first ring has been identified to be crucial for inhibiting 5-LOX. Therefore, the present study opened new avenues of developing low-molecular-weight anti-inflammatory agents with better pharmacokinetic and pharmacodynamics attributes....
In the previous research done, the anti-inflammatory perspectives of the 10,13-dimethyl-6-methylheptan-2-yl)-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) derivatives; (R,3E,7E)-((3R,10R,13R,14R)-10,13-dimethyl-17-((S)-6-methylheptan -2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17- tetradecahydro-1 H-cyclopenta[a]phenanthren-3-yl)-5-hydroxy-3-methyl-9-methyleneundeca-3,7-dienoate (1) and (E)-((3R,10R,13R,14R)-10,13-dimethyl-17-((S)-6-methylheptan-2-yl)-2,3,4,7,8, 9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-6-oxooct-4-enoate (2) as cyclooxygenase -2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors have been studied by docking approach using the GLIDE module of Maestro 9.1 software. In the continued research, the pharmacokinetic perspectives were studied to ensure that the drug will produce intended action without compromise in the bioavailability. By employing the QikProp module of the Maestro 9.1, the essential pharmacokinetic properties of both the compounds were studied exhaustively. The observed predicted parameters indicated that the molecules have quite compromised pharmacokinetics and are relatively toxic to cardiac tissues. The serum protein binding was found to be very high and the amount of free drug will be very low. The very high value of log P was detected and the molecules violated both the Lipinski Rule of 5 and Jorgensen Rule of 3. However, the predicted oral absorption was seen to be 100%, which is relatively noteworthy for exhibiting oral bioavailability. In addition to it, high values of Apparent MDCK and Apparent Caco-2 influence over the transporters and metabolic processes (Phase II conjugation enzymes) and also represented enhanced human intestinal absorption. The present study indicated that the further rational design of the molecules is required which will lead to better development of these analogs as drug moieties....
The LOXs converts arachidonic acid into thromboxane family, which are the most potent inflammatory and allergic mediator and enhances inflammatory responses and often precipitate unwanted chemical reactions which ultimately results in the aggravation of disease conditions like arthritis, bronchial asthma, inflammatory bowel disease (IBD), etc. In such an expedition, the ability of heterocycle pyran in inhibiting the LOX has been explored sensibly. The present research deals with the in-silico molecular docking based screening of two 2-substituted pyran molecules; (R)-2-(but-3-enyl)-tetrahydro-2H-pyran (1) and (R)-2-((S)-2-ethylbut-3-enyl)-3,6-dihydro-2H-pyran (2) against anti-inflammatory target activity LOX by utilizing Glide module of Maestro 9.1 software. A good molecular docking at the active site of 5-LOX was demonstrated where the ligands interacted with the enzymatic target with nearly identical dock Glide score of -6.92 Kcal/mol (1) and -7.17 Kcal/mol (2), respectively along with Van der Waals interactions of 953 and 1048. It was evident that both the pyran compounds formed a single stable hydrogen bonding via oxygen moiety with the polar amino acid residue Gln514 present in the active site cavity of 5-LOX. This study will be really being useful to the researchers across the globe who is working in the direction of inflammatory inhibitor development....
In the studies done so far, the potentials of two molecules of decahydrophenanthren-one scaffold; (4bS,7S,8aS)-1,1,4b-trimethyl-7-vinyl-1,4b,5,6,7,8,8a,9,10,10a-decahydrophenanthren-3(2H)-one (1) and (2R,4aR,7R,10aS)-7-hydroxy-2-vinyl-2,3,4a,4b,5,6,7,8,10,10a-decahydrophenanthren-4(1H)-one (2) as cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors of anti-inflammatory perspective have been established by induced-fit molecular docking method by using GLIDE module in Maestro 9.1 software. As pharmacokinetics properties are essential for the classes of drug to exhibit the desired time-bound pharmacological effect, in the current research, the crucial pharmacokinetics properties (total 33) of the two molecules were predicted and comprehensively studied by using the QikProp module of the Maestro 9.1 software. The present study focused on a number of pharmacokinetics cum toxicity parameters of compounds of decahydrophenanthren-one scaffold that have an influential role in mediating the pharmacodynamic effects. An amazing 100% oral absorption was predicted for both the compounds. The maximal transdermal transport rate and skin permeability values were noticed to be low and the alternative route seems to be irrelevant. A significantly high human intestinal absorption and cellular penetration may be predicted for both the compounds owing to the high (>500) values of Apparent MDCK and Apparent Caco-2. The ligand 1 was found to be privileged in terms of log P value, serum protein binding, CNS activity and Jorgensen Rule of 3. However, both the compounds followed Lipinski Rule of 5 and have the least chances of cardiotoxicity. Thus, the research will give ample directions for the rational design of novel decahydrophenanthren-one scaffold bearing molecules with better pharmacokinetics and toxicity attributes....
Aeromonas hydrophila is an emerging human pathogen which caused serious health problem regularly around the globe. The pathogen is common to seafood and fresh flowing, stagnant and brackish water. It is associated with hemorrhagic septicemia in cold-blooded animals including fish, reptiles and amphibians. The A. hydrophila bacterial DNA gyrase is the most validated intracellular anti-bacterial drug target with multiple prospective drug binding sites. In the present in vitro research, by utilizing the Maestro 9.1 software, we have validated two novel anti-bacterial compounds; (S)-3-((4aR,9R,10aS,10bS)-9-isopropyl- 4a,5,6,8,9,10,10a,10b-octahydro-2H-benzo[h]chromen-4-yl)-2-methylpropyl benzoate (1) and (4aR,6S,8S,8aR)-methyl-8-(2-(benzoyloxy)ethyl)-4-((E)-pent-2-en-1-yl)-4a,5,6,7,8,8a-hexahydro-2H-chromene-6-carboxylate (2) as A. hydrophilla DNA gyrase inhibitor (PDB ID: 1AJ6) by induced-fit docking (IFD) method. Here, the structure-based drug design (SBDD) approach was applied and the obtained Glide Score was reported. The current in-silico research revealed the perspectives of novel chromene based compounds as potential A. hydrophilla DNA gyrase inhibitors. Both the inhibitors absolutely bound to the active site. The inhibitors expressed hydrogen bonding interactions through / via- water molecules with the amino acid residues. Therefore, the inhibitors penetrated deeper into the active site cavity of the biological target and offer an enhanced orientation and can inhibit them corresponding to the active site. Therefore, the present research will unquestionably inspire the emerging medicinal chemists in developing potential anti- A. hydrophilla agents to overcome the prevailing resistance....
Most varieties of E. coli are harmless or cause relatively brief diarrhea. In contrast, the other strains that cause intestinal sickness. In E. coli, a number of anti-microbial targets have been identified by the researchers, from which fatty acid metabolism protein (FadR) is an emerging and attractive biological target to develop drug candidates. The FadR protein of E. coli has been shown to play a dual role in the transcription of the genes of bacterial fatty acid metabolism. Inhibition of E. coli FadR represents an effective way of controlling the infection. The present investigation involved in silico structure-based drug design (SBDD) screening of two chromene based molecules; (2R)-3-((9S,10aS,10bS)-9-isopropyl-4a,5,6,8,9,10,10a,10b-octahydro-2H-benzo[h]chromen-4-yl)-2-methylpropyl benzoate (1) and (4aR,6R,8R,8aS)-methyl-8-(2-(benzoyloxy)ethyl)-4-((E)-pent-2-en-1-yl)-4a,5,6,7,8,8a-hexahydro-2H-chromene-6-carboxylate (2) as E. coli FadR inhibitors by employing induced-fit docking technique using the Maestro 9.1 software. The present study involved identification of new chromene based compounds as potent anti-bacterial or more specific anti E. coli agents. It was clear from this research that both the compounds perfectly bound with the active site cavity of the biological target. The inhibitors demonstrated hydrogen bonding interactions directly as wells as through water molecules with the amino acid residues, and thus they could penetrate deeper into the active site cavity. These may provide the compounds a better orientation and can inhibit them complementary to the active site. Therefore, the research will undeniably motivate the modern day (medicinal) chemists and biologists to further explore and study the better halves of applications....
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