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1, 4-Dihydropyridine Calcium Channel Blockers: Homology Modeling Of Hindawi Publishing Corporation ISRN Medicinal Chemistry Volume 2014, Article ID 203518, 14 pages http://dx.doi.org/10.1155/2014/203518 Research Article 1,4-Dihydropyridine Calcium Channel Blockers: Homology Modeling of the Receptor and Assessment of Structure Activity Relationship Moataz A. Shaldam, Mervat H. Elhamamsy, Eman A. Esmat, and Tarek F. El-Moselhy Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt Correspondence should be addressed to Tarek F. El-Moselhy; [email protected] Received 28 September 2013; Accepted 5 December 2013; Published 10 February 2014 Academic Editors: R. B. de Alencastro, P. L. Kotian, O. A. Santos-Filho, L. Soulere,` and S. Srichairatanakool Copyright © 2014 Moataz A. Shaldam et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. +2 1,4-Dihydropyridine (DHP), an important class of calcium antagonist, inhibits the influx of extracellular Ca through 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. 1. Introduction DHP is the most feasible heterocyclic ring with various substitutions at several positions [8]. The discovery that Voltage-gated calcium channels play an integral role in the 1,4-dihydropyridine class of calcium channel blockers 2+ 2+ the entry of Ca ions into excitable cells and are also inhibits the Ca influx represents a major therapeutic involved in a variety of calcium-dependent processes, advance in the treatment of cardiovascular diseases, such including muscle contraction, hormone or neurotransmitter as hypertension, angina pectoris, and other spastic smooth release, gene expression, cell motility, cell division, and muscle diseases [9]. The most feasible position for sub- cell death [1, 2]. The isoform alpha-1C gives rise to long- stitution is the 4-position which exhibits various calcium lasting (L-type) calcium currents. They are blocked by 1,4- channel antagonist activities [10] and the heterocyclic ring dihydropyridines (DHPs) such as nifedipine, phenylalky- is the common feature for various pharmacological activities lamines such as verapamil, and benzothiazepines such as such as antihypertensive, antianginal [11, 12], antitumor [13], diltiazem [3]. Voltage-dependent calcium channels are mul- anti-inflammatory activity [14, 15], antitubercular activity tisubunit complexes, consisting of alpha-1, alpha-2, beta, [16], analgesic activity [17]andantithrombotic[18, 19]. It and delta subunits in a 1:1:1:1 ratio. The channel activ- binds to L-type channel and also shows action by binding ityisdirectedbythepore-formingandvoltage-sensitive to N-type channel [20]. The DHP class of compounds, alpha-1 subunit. In many cases, this subunit is sufficient in which nifedipine is the prototype, has been the aim to generate voltage-sensitive calcium channel activity that of many structure-activity relationship studies [21–28]. 1,4- displaysthemajorelectrophysiologicalandpharmacolog- DHP nucleus is capable of recognizing comparatively small ical properties of the full-fledged heteromeric channels [4–7]. 2 ISRN Medicinal Chemistry 1102030405060 2A9H A LLLLHWRAAG AAT VVLVI LLA GGSEY AA V R AAAP G ------- LLISYPDA WWS VETAT TV model IIKKKAMVVP L L HHA L LLFV IIIY A IIG LLE FM G M TC Y N G I TN FFFD N A AM L T V FQCI TME 70 80 90 100 110 120 2A9H G YGDLYPVT - ----- L WGRCVA VVVMVAGI TSYGLVFAAVA T WF V G - R E Q A L HWR A A G AAT model GWTDDV L Y WV NAVGRDW PWI Y FVT L I I IGSFF VLN LVLGV L S G E F SKE R E L N S V R S I AS L L 130 140 150 160 170 180 2A9H V L L V I V L L A G S Y L A V L A E R - G A P G A A - - - - - - - L I S Y P DA L WWS V E TA T T V G Y GD L Y P V T - model L L L F L F I I I F S L L GMQ L F G G K F N F D E MQ T R R S T F DN F P QS L L T V F Q I L T G E DWNS V M Y D G I 190 200 210 220 230 240 2A9H - --------- LWGRCVAVVVMVAG I T S Y G L V F A A V A T WF V G R E Q A L HWR A AAAG TVLLVIV model MAYGG P SFPGMLVCI YF I I LF ICG N Y I L L N V F L A I A V DN L A D A E F V A I R T I G NI VIVTTLL 250 260 270 280 290 300 2A9H LLAGSYL AV L A E R G A P G A A ------ - L I S Y P D A L WWSV E T A T T V GYGDLY PVT - - - --- - - model Q FMFAC I G V Q L F K G K L Y T CSDS SKFDF DN V L A AMM A L F TVSTFEGWP E L L YRS IDSHTEDK 310 320 330 340 350 360 2 9 A H -------L WG R C V AVV V MV A G I T S Y G L V F A A V A TW FV G R E QA L HWR A A G AA T V L L V I V L L A model GP I YNYRVE I S I F F I I Y I I I I A F FMMN I FV G F V I V T F Q E Q G I K S F Q A L P YV A L L I VM L F F I 370 380 390 400 410 420 2A9H G S Y LAVL A ER - G A PGAA - - - - - - --LI S YPD A L WWSV E TAT T V GYGD L YPV T - ---- - --- model YGAVI GMQV F K IALNDT T E I NPRNNNFQ T F QAAVL L L F R C TLGEAWQD I M APCMP GKK C A E 430 440 450 460 470 480 2A9H - --------------LWG R C V A VVVMV A G I T S Y G L V F A A V A TW F V G REQ model SEPSNSTEGETPCGSSFA VFYF ISF Y ML C A F L I I N L F V A V I MD N F D Y L T Figure 1: Sequence alignment between the amino acid sequence of model and that of KcsA. Red lines are chain break, dashes are inserted gabs, color code: blue = identical, sky blue = similar (color intensity decreases with similarity decrease), and white = no similarity; model = DHP receptor model amino acid sequence; 2A9H = the amino acid sequence of the template KcsA; numbers from 1 to 480 are amino acid sequence ruler. differences in sequence associated with the generation of atoms in their closed conformation were downloaded from 2+ Ca channels splice variants [29]. the RCSB Protein Data Bank (code 2A9H) [33]. Amino acid The number of known protein sequences is 50 times as sequences of S5, S6, and P-loops in between for the four that of the 3D protein structures. This gap hinders evolution repeats (I–IV) (262–413, 645–760, 1023–1173, and 1354–1483, in many areas of biochemistry because a protein sequence resp.) were used for sequence alignment with the amino acid provides little meaning outside the context of its 3D structure. sequence of KcsA as proposed by Zhorov et al. [34](c.f. The disparity is less severe than the numbers might suggest Figure 1). because different proteins often adopt similar 3D folds [30]. In order to favor valid superimposition of the residues, As a result, each new protein structure can serve as a model the sequence of each repeats was organized as S5, S6, and for other protein structures. As an approach to understand P-loop,allowingforamoreflexibleinspectionoftheresults the mechanism of action of DHPs, splicing veracity, and and easier corrections (c.f. Table 1). The amino acid sequence 2+ selectivity, 3D structure of L-type voltage-gated Ca channel of repeats I and III, has long extracellular loop which would alpha-1C was developed by means of homology modeling. decrease the quality of the generated model, so amino acid Furthermore, SAR of DHP was reviewed, summarized, and sequences (301–341 and 1064–1095) were excluded from discussed. repeats I and III, respectively. Since the template is 88 residues shorter than the target protein, gaps were inserted to achieve best sequence similarity and identity without 2. Experimental Protocol affecting sequence alignment proposed by Zhorov et al.34 [ ]. The protocol used to develop the DHP model is divided into three phases: sequence alignment, model construction, and 2.2. Construction of the DHP Receptor Model. The modeling model evaluation. procedure consisted of two steps: model construction from template and refinement of loops. The above described 2.1. Sequence Alignment. The model was constructed using sequence alignment file was used as input for the MOD- amino acid sequence of voltage-dependent L-type calcium ELLER 9v4 program [35] with the high-resolution NMR channel subunit alpha-1C (code CAC1C HUMAN Q13936 structure of potassium channel KcsA available in the RSCB isoform 20) obtained from UniProtKB/Swiss-Prot sequence ProteinDataBank(PDBentry2A9H)astemplateforthe database [31, 32].
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