1,4-Dihydropyridine (DHP), an important class of calcium antagonist, inhibits the influx of extracellular Ca+2through L-type voltage-dependent calcium channels. Three-dimensional (3D) structure of calcium channel as a receptor for 1,4-dihydropyridine is a step in understanding its mode of action. Protein structure prediction and modeling tools are becoming integral parts of the standard toolkit in biological and biomedical research. So, homology modeling (HM) of calcium channel alpha-1C subunit as DHP receptor model was achieved. The 3D structure of potassium channel was used as template for HM process. The resulted dihydropyridine receptor model was checked by different means to assure stereochemical quality and structural integrity of the model. This model was achieved in an attempt to understand the mode of action of DHP calcium channel antagonist and in further computer-aided drug design (CADD) analysis. Also the structure-activity relationship (SAR) of DHPs as antihypertensive and antianginal agents was reviewed, summarized, and discussed.
Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC 50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3-and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure-activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr) 4311 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3-and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.Key words calcium channel; dihydropyridine; docking; synthesis; three-dimensional quantitative structureactivity relationship (3D-QSAR) Precise regulation of calcium homeostasis is crucial for many physiological functions.1) Divergent types of calcium channels and pumps can control the influx of calcium ions into cells.2,3) Consequently, targeting calcium channels is advantageously beneficial to yield useful drugs. Ca V 1.2 blockers can be roughly categorized into three different chemical classes: 1,4-dihydropyridine (DHP) derivatives, phenylalkylamine derivatives and benzothiazepine derivatives. Among them, DHP derivatives have the most significant pharmacological importance. For example, amlodipine is among the top-five best selling drugs in the treatment of cardiovascular diseases. Various modulators can potentiate or block calcium entry through L-type calcium channels. [4][5][6] Calcium antagonists have a versatile pharmacological activity such as antihypertensive and antianginal, 7-9) antitumor, 10,11) anti-inflammatory, 12,13) antitubercular, 14,15) anticonvulsant and antithrombotic. 16,17) 1,4-DHPs bind selectively to L-type calcium channel protein, precisely at the transmembrane domain IIIS6 and IVS6 regions of the α1 subunit.18) The twelve approved DHP calcium antagonists developed are vasodilators.19) Vasodilatation is due to the uncoupling of the contractile mechanism of vascular smooth muscle, which requires Ca 2+ . 20)Structure-activity relationship (SAR) of DHP 21) and the clinical usage of nifedipine have promoted us to synthesize two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking st...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.