Docking and scoring in virtual screening for drug discovery: Methods and applications. Nat. Rev. Drug Discov. 3, 935-949

Department of Computer-Aided Drug Discovery, Albany Molecular Research, Inc., 21 Corporate Circle, Albany, New York 12212-5098, USA.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 12/2004; 3(11):935-49. DOI: 10.1038/nrd1549
Source: PubMed

ABSTRACT Computational approaches that 'dock' small molecules into the structures of macromolecular targets and 'score' their potential complementarity to binding sites are widely used in hit identification and lead optimization. Indeed, there are now a number of drugs whose development was heavily influenced by or based on structure-based design and screening strategies, such as HIV protease inhibitors. Nevertheless, there remain significant challenges in the application of these approaches, in particular in relation to current scoring schemes. Here, we review key concepts and specific features of small-molecule-protein docking methods, highlight selected applications and discuss recent advances that aim to address the acknowledged limitations of established approaches.

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    • "The first one is an aaNAT product and shows that this enzyme holds a special place in the insect cuticle sclerotization [24] [25]. Molecular Docking studies allow us to analyze the orientation of the molecule (ligand/inhibitor), describing the affinity of a given molecule to a protein-binding site [26]. Virtual screening of chemicals is one of the main techniques currently used in Drug Discovery, testing natural and synthesized compounds [27] [28]. "
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    • "In the main, there are two aims of docking studies: accurate structural modeling and correct prediction of activity. However, the identification of molecular features that are responsible for specific biological recognition, or the prediction of compound modifications that improve potency, are them are much more focused on capturing energetic than entropic effects (Kitchen et al., 2004; Dash R, 2014). "
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    ABSTRACT: Developing a new agent in the anti-inflammatory and analgesic field, plants secondary metabolites can be a good source for the Non-Steroidal Anti-inflammatory Drugs (NSAID) drug development. For this purpose we subjected the active compounds of Mimosa pudica Linn. to reveal its potentiality by molecular docking analysis to find out its potent compound against COX which was done by GOLD docking analysis. Docking studies by GOLD showed that vitexin of Mimosa pudica had the highest fitness score against the COX-1 which is 60.43 and 63.49 for COX-2 enzyme. Vitexin of Mimosa pudica detected with significant fitness score and hydrogen bonding against COX-1 and COX-2 which may be a potent analgesic compound.
    Journal of Applied Pharmaceutical Science 08/2015; 5(07):71-75. DOI:10.7324/JAPS.2015.50712 · 0.47 Impact Factor
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    • "In addition to search algorithms, scoring functions have been used to predict the biological affinity through the evaluation of interactions between compounds and potential targets (Kitchen et al., 2004). The scoring functions consist of equations to treat electrostatic and Van der Waals interactions, and inclusion of at least some solvation or entropic effects (Gohlke and Klebe, 2002; Kitchen et al., 2004). This methodology has been applied with great success in the prediction of bound conformations of enzyme–inhibitor complexes, peptide–antibody complexes, and even protein–protein interactions (Gambhir et al., 2014; Mladenovic et al., 2013; Morris et al., 2009). "
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    ABSTRACT: The relaxant effect of 8(17),12E,14-labdatrien-18-oic acid (LBD) was investigated on isolated aortic rings and compared with forskolin (FSK), a standard and potent activator of adenylyl cyclase (AC) with relaxing effect. The presence of potassium channel blockers, such as glibenclamide (ATP-blocker), apamin (SKCa-blocker), charybdotoxin (BKCa-blocker) did not significantly affect either the LBD or FSK concentration-response curves. However, in the presence of 4-aminopyridine (KV-blocker), the relaxant effect for both diterpenes was significantly attenuated, with reduction of its relative potencies. Moreover, the relaxation induced by 8-Br-cAMP, an analog of cAMP, was also significantly attenuated in the same conditions, i.e., in the presence of 4-aminopyridine. The presence of aminophylline, a nonselective phosphodiesterase inhibitor, caused a significant increasing in the potency for both LBD and FSK. On the other hand, the presence of Rp-cAMPS, a selective PKA-inhibitor, significantly attenuated the relaxant effect of LBD. In this work, in the same experimental conditions, both labdane-type diterpenes presented remarkably similar results; FSK, however, presented a higher potency (100-fold) than LBD. Thus, the hypothesis that LBD could be a novel AC-activator emerged. To assess that hypothesis, computational molecular docking studies were performed. Crystallographic structure of adenylyl cyclase/forskolin complex (1AB8) was obtained from RSCB Protein Data Bank and used to compare the modes of interaction of the native ligand and LBD. The computational data shows many similarities between LBD and FSK concerning the interaction with the regulatory site of AC. Taken together, the results presented here pointed to LBD as a novel AC-activator. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 07/2015; 764. DOI:10.1016/j.ejphar.2015.06.063 · 2.53 Impact Factor
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