Pharmaceutical Chemistry
A Bioinformatics Approach for Homology Modeling and %LQGLQJ6LWH,GHQWL¿FDWLRQRI7ULRVHSKRVSKDWH,VRPHUDVHIURP Plasmodium falciparum 3D7
Ullah M, Hira J1, Ghosh T, Ishaque N, Absar N
Department of Biochemistry and Biotechnology, University of Science and Technology Chittagong (USTC), Bangladesh, 1Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
Address for correspondence: Mr. M. Ullah, E-mail: [email protected]
ABSTRACT
Malaria is a major public health concern, and malarial parasites have developed resistance against the commonly DYDLODEOHGUXJV6RQRZDGD\VLWLVDPDMRUFRQFHUQWR¿QGRXWDQHZWDUJHWIRUGUXJWKHUDS\Plasmodium falciparum 'RQHRIWKHVWUDLQVRISODVPRGLXPVSHFLHVDOVRODFNVLQDIXQFWLRQDOWULFDUER[\OLFDFLGF\FOHDQGVROHO\GHSHQGHQW RQJO\FRO\VLVIRULWVHQHUJ\VXSSO\OLNHRWKHUSODVPRGLXPVSHFLHV$OWKRXJKHQ]\PHVRIPDODULDOSDUDVLWHKDYHEHHQ considered as potential antimalarial drug targets, a little is known about their structural biology. The tertiary structure of triose phosphate isomerase of P. falciparum 3D7 was determined by means of homology modeling through multiple DOLJQPHQWIROORZHGE\LQWHQVLYHRSWLPL]DWLRQDQGYDOLGDWLRQ7KHPRGHOLQJZDVGRQHE\6ZLVV0RGHO:RUNVSDFH 7KHREWDLQHGPRGHOZDVYHUL¿HGZLWKWKHVWUXFWXUHYDOLGDWLRQSURJUDPVVXFKDV352&+(&.9HULI\'DQG40($1 IRUUHOLDELOLW\7KHYHULI\'YDOXHRI LQGLFDWHVWKDWWKHHQYLURQPHQWSUR¿OHRIWKHPRGHOLVJRRG$VHOIRSWLPL]HG SUHGLFWLRQPHWKRGZLWKDOLJQPHQWRU6230$LVHPSOR\HGIRUFDOFXODWLRQRIWKHVHFRQGDU\VWUXFWXUDOIHDWXUHVRI triose phosphate isomerase. The secondary structure indicates that the predicted 3D structure of triosephosphate isomerase of P. falciparum'FRQWDLQVDKHOL[ UDQGRPFRLODQGH[WHQGHGVWUDQG$FWLYH VLWHGHWHUPLQDWLRQWKURXJK&$67SVXJJHVWVWKDWWKLVSURWHLQFDQEHXWLOL]HGDVDSRWHQWLDOGUXJWDUJHW+RZHYHU these will further be tested by wet lab studies for a targeted vaccine design against P. falciparum 3D7.
Key words: Active site, homology modeling, Plasmodium falciparum 3D7
INTRODUCTION LWDPDMRUFDXVHRI KXPDQPRUELGLW\DQGPRUWDOLW\ ZRUOGZLGH>@7KHGLVHDVHLVFDXVHGE\WKHSDUDVLWHVRI 0DODULDDIÁLFWVPLOOLRQSHRSOHHDFK\HDUPDNLQJ the Plasmodium species (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae DQG Access this article online LVWUDQVPLWWHGE\IHPDOHPRVTXLWRRI WKH$QRSKHOHV Quick Response Code: genus.>@ P. falciparum is the most virulent of the four Website: www.jyoungpharm.in species causing malaria and responsible for most PDODULDOGHDWKV7KHSDUWLFXODUYLUXOHQFHRI P. falciparum
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262 Journal of Young Pharmacists Vol 4 / No 4 Ullah, et al +RPRORJ\PRGHOLQJDQGELQGLQJVLWHLGHQWL¿FDWLRQRIWULRVHSKRVSKDWHLVRPHUDVH isomerase of P. falciparum 3'%FRGH <'9B$ >@ Secondary structure and active site of triosephosphate isomerase 3D-model Analysis of secondary structure 7KH'VWUXFWXUHRI WULRVHSKRVSKDWHLVRPHUDVHRI P. falciparum 7KHVHFRQGDU\VWUXFWXUHDQDO\VLVLVXVHGWRNQRZ 'ZDVEXLOWE\KRPRORJ\PRGHOLQJEDVHGRQWKHWHPSODWH ZKHWKHUDJLYHQDPLQRDFLGOLHVLQDKHOL[VWUDQGRUFRLO ZKLFKLVREWDLQHGIURPSURWHLQGDWDEDQN>)LJXUH@ 6HFRQGDU\VWUXFWXUDOIHDWXUHVDVSUHGLFWHGXVLQJ6230$ DUHUHSUHVHQWHGLQ7DEOH7KHVHFRQGDU\VWUXFWXUHDUH Validation of model SUHGLFWHGE\XVLQJGHIDXOWSDUDPHWHUV ZLQGRZZLGWK VLPLODULW\WKUHVKROG DQGQXPEHURI VWDWHV Validation of the structure 7KHƶ and ƸGLVWULEXWLRQYDOXHRI WKH5DPDFKDQGUDQSORW Active site determination RI QRQJO\FLQHDQGQRQSUROLQHUHVLGXHVDUHVKRZQLQ 7KHDFWLYHVLWHRI WULRVHSKRVSKDWHLVRPHUDVHRI P. falciparum )LJXUHDQG7DEOH 'ZDVSUHGLFWHGE\XVLQJ&$67SVHUYHU>)LJXUHD@ )XUWKHULQWKLVVWXG\ZHKDYHDOVRUHSRUWHGWKHEHVWDFWLYH 9HULÀFDWLRQRI WKH'PRGHO VLWHDUHDRI WKHH[SHULPHQWDOHQ]\PHDVZHOODVWKHQXPEHU 7KHSURÀOHVFRUHDERYH]HURLQWKH9HULI\'JUDSKFRUUHVSRQG RI DPLQRDFLGLQYROYHGLQLW>)LJXUHE@ WRWKHDFFHSWDEOHHQYLURQPHQWRI WKHPRGHO>)LJXUH@7KH JOREDOTXDOLW\RI WKHPRGHOIRUWKHWDUJHWVHTXHQFHZDV HVWLPDWHGE\WKH40($1VFRUHEDVHGRQOLQHDUFRPELQDWLRQ DISCUSSION RI VL[VWUXFWXUDOGHVFULSWRUV>7DEOH@ZKLFKUHÁHFWVSUHGLFWHG 7KHKRPRORJ\PRGHOLQJDOJRULWKPKDVSURYHGWREHRQH PRGHOUHOLDELOLW\UDQJHVIURPWR>@7KHUDZ40($1 RI WKHPRVWUREXVWPRGHOLQJWRROVLQELRLQIRUPDWLFV7KH score and average ZVFRUHIRUWULRVHSKRVSKDWHLVRPHUDVHRI SURWHLQPRGHOEXLOWLQWKLVVWXG\E\XVLQJVWDQGDUGSURWRFRO P. falciparum'PRGHODUHVKRZQLQ)LJXUH LQGLFDWHVWKDWWKHHQ]\PHFRQWDLQVDKHOL[EVKHHWVDQG ORRSV7KHVWUXFWXUHPRGHOHGE\&3+PRGHOVVHUYHU
Figure 1: 3D model of triose phosphate isomerase of P. falciparum 3D7 by comparative modeling (Swiss Model Workspace) Figure 2: Ramachandran plot of triose phosphate isomerase of P. Table 1: Ramachandran plot statistics of falciparum 3D7 obtained through the modeling tool triosephosphate isomerase of 3IDOFLSDUXP 3D7 Rama chandran plot statistics (%) Table 2: Z scores of individual component of QMEAN for Residues in the most favored regions [A, B, L] 204 90.3 WULRVHSKRVSKDWHLVRPHUDVH 3IDOFLSDUXP 3D7) models Residues in the additional allowed regions [a, b, l, p] 21 9.3 Scoring function term Z-score Residues in the generously allowed regions [a, b, l, p] 1 0.4 C_E interaction energy 0.16 Residues in the disallowed regions 0 0.0 All-atom pairwise energy í Number of non-glycine and non-proline residues 226 100 Solvation energy 1.72 Number of end-residues (excl. Gly and Pro) 2 Torsion angle energy í Number of glycine residues (shown in triangles) 14 Secondary structure agreement 0.12 Number of proline residues 4 Solvent accessibility agreement 0.46 Total number of residues 246 QMEAN6 score 0.00
Journal of Young Pharmacists Vol 4 / No 4 263 Ullah, et al +RPRORJ\PRGHOLQJDQGELQGLQJVLWHLGHQWL¿FDWLRQRIWULRVHSKRVSKDWHLVRPHUDVH
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310 helix 0.00
Pi helix 0.00 Beta helix 0.00 Extended strand 16.67 Beta turn 5.69 Bend region 0.00 Random coil 29.27 Ambiguous state 0.00 Other states 0.00
Figure 4: Graphical presentation of estimation of absolute quality of model triosephosphate isomerase (P. falciparum 3D7). The QMEAN Z scores were near “0” value for the model compared to the nonredundant set of protein structure. Here the dark zone indicates that the model has CQHUEQTG CPFVJGOQFGNVJCVJCUJCXGCUEQTGQH QT QT locates outside of this dark zone. Good models are generally located in the dark zone. The red marker indicates a query or a generated Figure 3: Verify 3D graph of triose phosphate isomerase (P. falciparum target model, which are considered to be a good model according to 3D7) their position near or in the dark zone
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266 Journal of Young Pharmacists Vol 4 / No 4