Frequency: Quarterly E- ISSN: 2278-4071 P- ISSN: IBI Factor: 4.2 Abstracted/ Indexed in: Ulrich's International Periodical Directory, Google Scholar, SCIRUS, Genamics Journal Seek, PSOAR, getCITED, InfoBase Index, EBSCO Information Services
Quarterly published in print and online "Inventi Rapid: Molecular Modeling" publishes high quality unpublished as well as high impact pre-published research and reviews catering to the needs of researchers and professionals. The journal includes all aspects of molecular modeling and computational chemistry, including study of molecular shape and properties, molecular simulations, protein and polymer engineering, drug design, materials design, QSAR, structure-activity and structure-property relationships, database mining, and compound library design.
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....
Fragment-based drug design has become an important and powerful tool for drug discovery. We present a review on the overview of the fragment-based drug design. We also discuss the novel approaches of fragment-based drug design (FBDD). FBDD is used for finding the lead compound and identifying the small chemical fragments, which may binds only to the biological target and produce a lead with a higher affinity....
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....
The objective of the current study is to evaluate the lipoxygenase inhibitory activity of flavonoids using in silico docking studies. In this perspective, flavonoids like Biochanin, Isorhamnetin, Tricetin, Tricin, and Okanin were selected. Azelastine, a known lipoxygenase inhibitor was used as the standard. In silico docking studies were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. Three important parameters like binding energy, inhibition constant and intermolecular energy were determined. The results showed that all the selected flavonoids showed lesser binding energy ranging between -3.77 kcal/mol to -3.07 kcal/mol when compared with that of the standard (-3.72 kcal/mol). Intermolecular energy (-4.96 kcal/mol to -4.86 kcal/mol) and inhibition constant (1.73 mM to 5.64 mM) of the ligands also coincide with the binding energy. All the selected flavonoids consist of benzopyran ring in its basic nucleus, which would have contributed to its lipoxygenase inhibitory activity. These molecular docking analyses could lead to the further development of potent lipoxygenase inhibitors for the treatment of inflammation....
Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. The review encompasses the different search algorithms and the scoring functions used in docking methods Limitations of current technologies as well as future prospects are presented. We attempt to introduce the latest developments in drug design based on computational techniques, including protein structure modeling, docking, binding site prediction, quantitative structureââ?¬â??activity relationship (QSAR), pharmacophore and molecular dynamics simulation. The fundamental issues and challenges involved in comparing various docking methods are discussed. Limitations of current technologies as well as future prospects are presented....
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....
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