4-Amino modified derivatives of cytidine towards interactions with the methyltransferase enzyme

Abstract

By the importance of exploring novel compounds for inhibiting the cancerous enzymes activities, this work was performed to recognize advantages of employing 4-amino modified derivatives of cytidine for participating in more efficient interactions with the methyltransferase (MTN) cancerous enzyme target. To this aim, four groups of modified models of cytidine were investigated in addition the original models to recognize the structural features and the corresponding activities. The 4-amino site of cytidine was functionalized by different carbon-based groups in linear and cyclic modes through a bridging peptide linkage. The models were optimized to reach the minimized energy structures by performing quantum chemical calculations and their interactions with the target were analyzed by performing molecular docking simulations. The obtained results of 4-amino modified derivatives of cytidine showed advantages of employing structural modifications to find structures with better molecular orbital based features. Formations of interacting complexes indicated that the additional of carbon-based groups helped to improve possibility of interactions between the substances in both of chemical and physical modes. As a remarkable achievement of this work, the model of cytidine with a phenyl group showed the best advantage of participating in interactions with the MTN target among all twenty five models of the investigated cytidine compounds.

Keywords

Cytidine enzyme inhibitor methyltransferase cancer in silico

1 Introduction

Modifications of chemical structures could lead to generation of new compounds with more specified features [1 –3]. Indeed, structure-activity relationship (SAR) is a concept of drug design for optimizing the structures of leading pharmaceutical/biological compounds to approach an expected activity and function [4 –6]. In this regard, several attempts have been dedicated to recognize those lead compounds with potent functions in biologically related systems [7 –9]. Indeed, developing biological active compounds have been always an important topic of research works [10 –12]. Accordingly, several methodological approaches have been developed to achieve the purpose of such biological complex systems [13 –15]. Both of experimental and computations methodologies have been employed for clarifying such concepts to produce novel compounds with more specified features [16 –20]. Cytidine, a nucleoside form of cytosine nucleobase in combination with the sugar group, has been seen appropriate for showing pharmaceutical functions especially towards the enzyme inhibitions [21]. To this aim, considerable efforts have been done to modify the original structure of cytidine for generating novel structures with more specified activities and functions in medications of various diseases [22 –25]. In this regard, the approach of computer-aided drug design (CADD) has been developed to make accurate estimations and predictions for the investigated lead compounds up to the recognition of their features and mechanism of actions [26 –30]. In silico medium has been introduced for achieving the purposes of CADD in addition to the already known in vitro and in vivo media [31 –33]. Three-dimensional geometrical shapes of chemical compounds and their branched functional groups could both show variations in their resulting activities [34]. Therefore, it is indeed a must to carefully recognize the characteristic features of the own chemical structure and its corresponding activity against the targeted enzyme macromolecules [35 –37]. Both of quantum chemical calculations and molecular docking simulations methodologies could help to achieve the purpose of in silico drug design approach [38 –40].

Cytidine (Fig. 1) has been expected to inhibit the activity of cancerous enzymes, in which several works showed its feasibility for the methyltransferase enzyme inhibition [41 –43]. In this regard, modifications of cytidine have been proposed for achieving more efficient enzyme inhibition function [44 –46]. The heterocyclic purine ring of cytidine has appropriate atomic sites for being functionalized by other groups [47 –49]. For example, the atomic carbon number five of purine ring is a suitable atomic site for functionalization by halogen atoms, in which such advantage was seen for the well-know 5-fluorouracil anticancer [50 –52]. Moreover, the sugar group has been seen suitable for chemical modification to obtain desired structures [53]. In the current research work, the amine group of cytidine was modified by additional of carbon-based groups in chain and cyclic forms through formation of a peptide linkage (Fig. 1). Existence of such peptide linkage for cytidine was reported by earlier works [54]. To this aim, up to six carbon atoms with different configurations were added to the peptide group to produce new compounds of cytidine. As mentioned for the benefits of in silico drug design approach, this work was done by employing the computational molecular models and calculations to provide the required results [55 –58]. Indeed, several methods have been always under developments for investigating both of food and drug cases, in which several protocols have been improved to this time [59 –63]. Cancer is an important issue of research works, in which so many people are always in trouble with the serious negative impacts of various types of cancers [64 –66]. Therefore, it is important to optimize the cancerous inhibitors for showing more efficient functions [67 –69]. In a brief definition of the main goal of this work, it should be mentioned that the structural modification of cytidine at the amine site of purine ring was done to obtain new ligand compounds and their functions against the methyltransferase macromolecular target were examined in the in silico medium to approach more efficient inhibitors of the cancerous enzymes.

Fig. 1

The original cytidine (top) and the 4-amino derivatives template (bottom).

2 Materials and methods

Materials of this work were the small molecular structures of cytidine (ligand) and the macromolecular structure of methyltransferase (target), in which their three-dimensional geometries were included in the computations. Methods of this work were the quantum chemical calculations to optimize geometries of the ligand structures and the molecular docking simulations to provide the formation of ligand-target complexes. In this type of study, molecular models are very important to prepare the required materials, in which three-dimensional models are used for achieving this purpose. Accordingly, mathematical algorithms, physical concepts, and computer-facilities could kelp to run the desired computations on the models in the in silico medium. To obtain the ligand structures, the amine group of purine ring of cytidine was functionalized by other carbon-based groups through a peptide linkage (Table 1 and Fig. 1). The carbon chains were consisting of one to six carbon atoms in linear and cyclic configurations for being attached to the amine group of cytidine. Moreover, unsaturated forms of carbon chains were considered to show benefits of existence of such bonds in the features of ligands and their corresponding activity against the target. Density functional theory (DFT) calculations were performed using the Gaussian program, in which the B3LYP/6-31 + G^* level was employed for running the calculations [70]. Molecular docking simulations were performed using the HDock webserver to recognize the formation of interacting ligand-target complexes [71]. The color description of molecular docking results were exhibited in Fig. 2. The three-dimensional structure of original cytidine was obtained from the ChemSpider structural bank with code 5940 and other structures were drawn by modification of the amine group [72]. The three-dimensional structure of original methyltransferase was obtained for the Protein Data Bank (PDB) with code 2qrv and it was prepared for participating in interacting ligand-target complex formations by eliminating the extra components [73]. For the ligand structures, chemical descriptors such as ionization potential (IP), electron affinity (EA), chemical hardness (CH), chemical softness (CS), and dipole moment (DM) were evaluated (Table 1). Moreover, graphical representations of distribution patterns of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were exhibited for the optimized ligand models (Figs. 3–7). Next, the obtained results of molecular docking simulations were evaluated for showing the strength of ligand-target complex formations by means of the obtained docking SCORE values and they were ordered by the RANK values. All quantities were listed in Table 1. Furthermore, surrounding amino acids of ligands and their interacting types were visualized for reaching a qualitative analysis of the models (Figs. 3–7).

Table 1
Molecular features of the 4-amino modified derivatives of cytidine compounds

Compound R Group IP EA CH CS DM SCORE RANK

Original

C1 n/a 6.63 1.31 2.66 0.38 3.34 –147.92 25

C2 H 6.94 2.15 2.39 0.42 2.77 –152.85 23

Group 1

C3 CH₃ 6.82 1.96 2.43 0.41 3.41 –160.23 4

C4 C₂H₅ 6.79 1.92 2.44 0.41 3.40 –156.82 12

C5 C₃H₇ 6.79 1.91 2.44 0.41 3.38 –153.46 19

C6 C₄H₉ 6.78 1.91 2.44 0.41 3.46 –152.88 22

C7 C₅H₁₁ 6.78 1.90 2.44 0.41 3.40 –152.45 24

C8 C₆H₁₃ 6.78 1.90 2.44 0.41 3.48 –156.07 13

Group 2

C9 C₂H₃ 6.81 2.39 2.21 0.45 3.45 –157.30 11

C10 C₃H₅ 6.83 2.02 2.41 0.42 3.10 –154.73 17

C11 C₄H₇ 6.83 1.99 2.42 0.41 3.04 –160.12 5

C12 C₅H₉ 6.81 1.95 2.43 0.41 3.13 –153.63 18

C13 C₆H₁₁ 6.80 1.93 2.44 0.41 3.15 –155.16 16

C14 C₆H₉ 6.44 1.99 2.22 0.45 2.98 –160.42 3

C15 C₆H₇ 6.54 2.74 1.90 0.53 5.02 –158.09 9

Group 3

C16 C₃H₅ 6.76 1.92 2.42 0.41 3.66 –158.46 8

C17 C₄H₇ 6.78 1.98 2.40 0.42 3.40 –155.73 15

C18 C₅H₉ 6.78 1.94 2.42 0.41 3.48 –153.20 20

C19 C₆H₁₁ 6.77 1.93 2.42 0.41 3.51 –160.03 6

Group 4

C20 C₃H₃ 6.74 1.91 2.42 0.41 3.78 –159.64 7

C21 C₄H₅ 6.80 1.96 2.42 0.41 3.29 –161.68 2

C22 C₅H₇ 6.81 1.99 2.41 0.42 3.11 –153.04 21

C23 C₆H₉ 6.80 1.97 2.42 0.41 3.35 –156.05 14

C24 C₆H₇ 6.79 1.95 2.42 0.41 3.24 –157.50 10

C25 C₆H₅ 6.78 2.23 2.28 0.44 4.12 –164.27 1

Compound	R Group	IP	EA	CH	CS	DM	SCORE	RANK
Original
C1	n/a	6.63	1.31	2.66	0.38	3.34	–147.92	25
C2	H	6.94	2.15	2.39	0.42	2.77	–152.85	23
Group 1
C3	CH₃	6.82	1.96	2.43	0.41	3.41	–160.23	4
C4	C₂H₅	6.79	1.92	2.44	0.41	3.40	–156.82	12
C5	C₃H₇	6.79	1.91	2.44	0.41	3.38	–153.46	19
C6	C₄H₉	6.78	1.91	2.44	0.41	3.46	–152.88	22
C7	C₅H₁₁	6.78	1.90	2.44	0.41	3.40	–152.45	24
C8	C₆H₁₃	6.78	1.90	2.44	0.41	3.48	–156.07	13
Group 2
C9	C₂H₃	6.81	2.39	2.21	0.45	3.45	–157.30	11
C10	C₃H₅	6.83	2.02	2.41	0.42	3.10	–154.73	17
C11	C₄H₇	6.83	1.99	2.42	0.41	3.04	–160.12	5
C12	C₅H₉	6.81	1.95	2.43	0.41	3.13	–153.63	18
C13	C₆H₁₁	6.80	1.93	2.44	0.41	3.15	–155.16	16
C14	C₆H₉	6.44	1.99	2.22	0.45	2.98	–160.42	3
C15	C₆H₇	6.54	2.74	1.90	0.53	5.02	–158.09	9
Group 3
C16	C₃H₅	6.76	1.92	2.42	0.41	3.66	–158.46	8
C17	C₄H₇	6.78	1.98	2.40	0.42	3.40	–155.73	15
C18	C₅H₉	6.78	1.94	2.42	0.41	3.48	–153.20	20
C19	C₆H₁₁	6.77	1.93	2.42	0.41	3.51	–160.03	6
Group 4
C20	C₃H₃	6.74	1.91	2.42	0.41	3.78	–159.64	7
C21	C₄H₅	6.80	1.96	2.42	0.41	3.29	–161.68	2
C22	C₅H₇	6.81	1.99	2.41	0.42	3.11	–153.04	21
C23	C₆H₉	6.80	1.97	2.42	0.41	3.35	–156.05	14
C24	C₆H₇	6.79	1.95	2.42	0.41	3.24	–157.50	10
C25	C₆H₅	6.78	2.23	2.28	0.44	4.12	–164.27	1

Fig. 2

The color descriptions of molecular docking results.

Fig. 3

The HOMO-LUMO distribution patterns and L ... T complexes of the original cytidine models.

Fig. 4

The HOMO-LUMO distribution patterns and L ... T complexes of the Group 1 models.

Fig. 5

The HOMO-LUMO distribution patterns and L ... T complexes of the Group 2 models.

Fig. 6

The HOMO-LUMO distribution patterns and L ... T complexes of the Group 3 models.

Fig. 7

The HOMO-LUMO distribution patterns and L ... T complexes of the Group 4 models.

3 Results and discussion

The original model of cytidine was shown in Fig. 1, in which the 4-amino group was modified by an additional keto group to make an amide type of functionalized model. The template of other modifications was also shown to emphasize on employing the modifications through formations of amide type linkages. In this regard, the original cytidine and its first modification were assigned by C1 and C2 ligand models of Table 1.

Other modified models of cytidine were categorized in four groups based on the type of additional group to the already modified peptide linkage. The criterion of employing modifications was to include carbon groups from one to six carbon atoms in both of linear and cyclic models in saturated and unsaturated modes. To this aim, the models of Group 1 including C3-C8 compounds were created by additional of one to six carbon atoms in the saturated linear chains. The models of Group 2 including C9-C15 compounds were created by additional of two to six carbon atoms in the unsaturated linear chains, in which three unsaturated modes were assigned for the six carbon atoms chains. The models of Group 3 including C16-C19 compounds were created by additional of three to six carbon atoms in the cyclic forms with saturated modes. The models of Group 4 including C20-C25 compounds were created by additional of three to six carbon atoms in the cyclic forms with unsaturated modes, in which three unsaturated modes were assigned for the six carbon atoms cyclic groups. As a consequence, twenty five compounds of cytidine were prepared for the models of this work including the original models and four groups of 4-amino-modified derivatives. The models were optimized to obtain the minimized energy geometers for all of twenty five compounds. The molecular specifications of the models were tabulated in Table 1 exhibiting the category of compounds, the additional R group, molecular orbital based features of ionization potential (IP), electron affinity (EA), chemical hardness (CH), and chemical softness (CS), in addition to the evaluated values of dipole moment (DM). Moreover, molecular docking features including SCORE and RANK features were included in Table 1. The term of SCORE stands for the energy strength of complex formations of ligand ... target (L ... T) interacting systems and the term of RANK stands for the priority of formation of each complex system of interacting ligand in comparison with each other. It is worth to mention that the types of colorful interactions of molecular docking processes were described in Fig. 2 for assigning each color to each interaction type. Not only one type of interactions, but also several types of interactions were involved in the complex formations processes. In this regard, the strength of such interactions could be difined by their types and geometrical orientations. The molecular systems for each of original and Groups 1–4 were exhibited in Figs. 3–7 including the HOMO-LUMO distribution patterns and the interacting L ... T complex systems. To this point, all required results were prepared to analyze the 4-amono-modified derivatives of cytidine towards the methyltransferase (MTN) enzyme macromolecular target.

The models representations of original cytidine compounds, C1 and C2, were visualized in Fig. 3 including the HOMO-LUMO distribution patterns and interacting L ... T complex systems. Their molecular features were listed in Table 1. It is important to mention than the values of each level of HOMO and LUMO could show electronic features of the molecular models for participating in electron transferring processes. In this regard, the highest occupied and the lowest unoccupied molecular orbitals are those full and vacant places for participating in electron transferring processes as indicated by the HOMO and LUMO levels. The C1 compound is the cytidine molecule without any modification to the 4-amino group whereas the group was modified by additional of one keto group for creating the amide type linkage in the C2 compound. In this case, the evaluated distribution patterns could show occurrence of slight changes to the HOMO distribution patterns of C1 and C2 whereas the LUMO distribution patterns were remained almost unchanged. However, the interactions environments could show more significant results regarding the types of interactions, numbers of interactions, and the interacting amino acids and the molecular sites of interactions. It could be seen that the 4-amino-modifed region could make suitable the C2 model compound for participating in more favorable interactions with the surrounding amino acids in comparison with the C1 model compound. More specifications could be found by the evaluated features of Table 1 showing that both of IP and EA levels were increased in the C2 model compound. Moreover, the values of CH and CS indicated better suitability of the C2 model compound for contribution to other reactions in comparison with the c1 model compound. As a consequence, the docking SCORE and RANK of the C2 compound in the L ... T interacting complex formation were found more suitable than the C1 compound I the same condition. For such complex systems, observation of common amino acids such as characteristic TRP889 could affirm that the ligand models were interacting in a similar region of the enzyme macromolecular target. This trend is an important achievement regarding the interacting sites of macromolecular targets, in which variations from a similar interacting region could put significant changes for the models systems. As a consequence, the surrounding amino acids could affirm such similarity of the interacting regions. Moreover, both types of hydrogen bond and non-hydrogen bond interactions were observed for the models. As could be found by vales of DM, the new 4-amino group made a better charge balance for the C2 model and more numbers and types of interactions were found for the L ... T interacting complex systems. Indeed, the values of DM could show electric charge distribution balance at the molecular surface, in which its value could show deviation from such balance. The C1 model compound was placed at RANK 25 and the C2 model compound was placed at RANK 23 among all twenty five compounds. This trend seems to be enough for showing the need of employing structural modifications for approaching better features for the cytidine molecular compound. Indeed, the field of exploring availability of new anticancer compounds is a non-stop process regarding the importance of medications of cancerous patients by non-invasive protocols with the lowest occurrence of unwanted side effects.

The models of Group 1 of 4-amino modified derivatives of cytidine, C3-C8, were created by additional of the linear saturated chains of one to six carbon atoms to the R group of derivatives template of Fig. 1. The models were optimized to reach the minimized energy structures and their HOMO-LUMO distribution patterns and L ... T complex systems were exhibited in Fig. 4. As mentioned above, modifying the R group of original cytidine was done for obtaining more suitable ligand compounds for participating in better interactions with the MTN enzyme macromolecular target. In this regard, the values of SCORE and RANK could imply for showing such suitability for the derivatives compounds in comparison with the original compound even among the own derivatives compounds. The HOMO-LUMO distribution patterns of Fig. 4 indicated that the localizations of such frontier molecular orbitals were done mostly on the original cytidine scaffold and the modified chains were indeed free of availability of such localizations. Observing the interacting L ... T complex systems could affirm participations of carbon chain in few interactions with the surrounding amino acids, but the values of SCORE and RANK could indicate that the models were still more suitable that the original cytidine compound, C1. The compounds of Group 1 were ranked in this order C3 > C4 > C8 > C5 > C6 > C7. Interestingly, the C8 compound, with a chain of six carbon atoms, showed occurrence of a covalent bond formation in the carbon chain region by CYS706 in addition to availability of other interactions with the surrounding amino acids. It is important to mention that the ligand inhibitors could participate in reversible or irreversible interactions with the macromolecular targets, in which formations of covalent bonds could lead to occurrence of irreversible interactions as seen for the C8 compound. Based on the color descriptions of Fig. 2, interactions types of hydrogen bond and non-hydrogen bond were available for the complex formations and the characteristic TRP889 was surrounding the ligand compounds in all models affirming the similarity of interactions regions of the macromolecular target. Examining the values of Table could show that the models of Group 1 were detected slight effects of additional of various chain group among each other regarding their values of molecular orbital features including IP, EA, CH, and CS and even the values of DM. However, such features were significantly different from the original cytidine model showing the benefit of employing carbon chains modifications for the models systems to obtain better interactions efficiency.

The models of Group 2 of 4-amino modified derivatives of cytidine included unsaturated linear chains of two to six carbon atoms to the R group of derivatives template of Fig. 1 as indicated by the C9-C15 models systems. In this regard, the ending carbon bonds were unsaturated by means of putting a double bond for ending the carbon chain. For the chains with two to five carbon atoms, only one double bond was existed whereas three models of double bond were included for the chain with six carbon atoms. The priority of double bond formation was to locate at the ending region of the chain, in which it was put closer to the original cytidine scaffold in each of C7 and C8 models with two and three double bonds, respectively. First, it could be obvious from Fig. 5 that the HOMO-LUMO distribution patterns were localized at the carbon chin region in contrast with those observations for the case of linear carbon chains of Group 1 activating the chain for participating in interactions with the surrounding amino acids. Accordingly, the evaluated features of Table 1 indicated that the models were significantly changed in terms of molecular orbitals features, in which all of IP, EA, CH, and CS were detected such variations. Totally, the evaluated features were in the way of easier contribution of models of Group 2 for contributing to other reactions. In this regard, the HOMO and LUMO distribution patterns of C14 were located in separated parts of the molecular models, in which such feature made the C14 compound as the most suitable one among the models of Group 2. Briefly, the models of this group were ranked in this order: C14 > C11 > C15 > C9 > C13 > C10 > C12. Totally, unsaturation of the additional carbon chains helped to improve the interacting possibility for the cytidine compounds of Group 2, in which the models were the C14 and C11 compounds with six and four carbon chains won the competition of participating in interactions with the MTN macromolecular target. It could be noted that the characteristic TRP889 was seen for all the interacting L ... T complex systems of Group 2. In contrast with the models of Group 1, covalent bonds were not seen for the models of Group 2 and all the models were participating in physical interactions, in which the types of hydrogen bond and non-hydrogen bond interactions could be seen be color description of Fig. 2. Accordingly, the models of this group could be considered for participating in reversible inhibitory activity. As a consequence, the 4-amino modified models by the unsaturated carbon chains were seen more suitable than the original models of cytidine compounds for participating in interactions with the MTN enzyme macromolecular target even totally working better than the models of Group 1 for achieving the purpose.

The models of Group 3 are modified by additional of cyclic models of carbon atoms to the R group of cytidine derivatives template of Fig. 1. In these models, C16-C19, there to six carbon atoms were included in the saturated cyclic models of carbon atoms. Accordingly, their HOMO-LUMO distribution patterns were visualized in Fig. 6 besides representing the interacting L ... T complexes formations. In contrast with the additional of linear chains of carbon atoms, these models were modified by the additional of cyclic models of carbon atoms. Accordingly, their features indicated differences in comparison with the models of both of Groups 1 and 2. The HOMO-LUMO distribution patterns of these models were localized almost at whole of the molecular surface of the models of Group 3. However, significant separated localizations between the HOMO and LUMO patterns were observed for the C19 compound model of cytidine in comparison with other models of this group. Comparing the values of SCORE and RANK could lead to such ranking order of complexes formations: C19 > C16 > C17 > C18. The characteristic TRP889 was also seen for all the L ... T complexes of this group. In this regard, the modified models with six and three carbon atoms were in better conditions of participating in interactions with the target. Moreover, the formation of covalent bond was seen for the C18 compound with the cyclic group of five carbon atoms again with the C706 amino acid of the target enabling this ligand compound for contributing to irreversible inhibition process. As a note for such 4-amino modified models, the modification provided possibility of formations of covalent bonds for the interacting substances, which was not available for the original cytidine compound, besides providing a condition for occurrence of better physical interactions. As could be found by the color description of Fig. 2, the models formations were occurred by assistance of both of hydrogen bond and non-hydrogen bond interactions. Analyzing the content of Table 1 also showed the variations of molecular orbital features of the investigated models. It is worth to mention that the hetero-atomic component of the original cytidine scaffold had the most significant role of assigning the molecular orbital features and the additional of carbon groups slightly changes such features. As a consequence, the modified models were ranked in better conditions by showing the features such as CH and CS for participating in more suitable interactions with the MTN target. Accordingly, varieties of levels of formations of L ... T interacting systems were found for the investigated complex models. As a consequence, the models of 4-amino modified cytidine ligand compounds by the saturated cyclic carbon atoms were seen still considerable for participating in efficient interactions with the MTN target.

The last group of the 4-amino modified derivatives of cytidine were created by the additional of unsaturated cyclic carbon atoms to make Group 4 of this work. The models with three to five carbon atoms were created by the additional of one double bond, C20, C21, and C22, and those with six carbon atoms were modified by including one, two, and three double bonds for C23, C24, and C25 models respectively. The characteristic TRP889 was also seen for all the L ... T complexes of this group affirming similarity and comparability of interacting sites of the MTN enzyme macromolecular target for the investigated ligand compounds of cytidine. The best interacting 4-amino modified ligand compounds of cytidine were placed in this group by assigning the C25 and C21 compounds as the first and second ligands among all twenty five ligands of cytidine with the highest efficiency of participating in interactions with the MTN enzyme macromolecular target. The own models of Group 4 could be ordered in this rank C25 > C21 > C20 > C24 > C23 > C22 for participating in interactions with the MTN target. It was obvious from the HOMO-LUMO distribution patterns that the modifications with localization of LUMO at the modified region could help for participating of the ligand compound in more efficient interactions with the target in comparison with those ligand models with LUMO distribution close to the original cytidine scaffold. Moreover, the unsaturated models of such carbon chains of cytidine derivatives could help to improve the efficiency of L ... T complexes formations by activating the additional groups for participating in further interactions with the MTN enzyme macromolecular target. Availability of various types of interactions were seen for the models systems of this group in accordance with color descriptions of Fig. 2. Furthermore, the covalent bond formation was seen for C23 with the CYS706 amino acid of the target emphasizing on the role of additional group for improving the interacting possibility of the ligand models. Based on the achieved results, the models of Group 4 were recognized to be in efficient interactions with the MTN enzyme macromolecular target. Careful analysis of content of Table 1 also showed effects of 4-amino group modifications on the molecular orbital features of the investigated models by improving tendency of the ligands for better participation in the interactions with the target.

Comparing the group models of this work together and with the original ones could show the impact of structural modification on next functions of the models against the target models. Details of modifications and their evaluated features could help to approach a point of recognizing the ligand structures for desired purposes of interactions with the target models. Accordingly, further analysis of the models in detecting their roles of interacting parts could push forward the achievements of structural modifications. In this work, the models of four groups were modified by addition of specified functional groups to see their effects on both of structural features and interacting profiles. As a consequence, based on the obtained results of Table 1 and details of Figs. 3–7, the models were categorized to qualify the investigated problem of the work.

4 Conclusion

The models of 4-amino modified derivatives of cytidine (C1-C25) were investigated in this work for examining their interactions with the MTN enzyme target. The results indicated that the additional of carbon-based groups in both of linear and cyclic models could improve the features of cytidine derivatives for participating in more efficient interactions with the target. The models were analyzed in both of structural and activity features. The obtained molecular orbital features indicated that the derivatives of cytidine could be seen more suitable for contributing to further reactions and interactions, in which such results were affirmed by the molecular docking achievements. By ordering the efficiency of ligands for participating in interactions with the MTN target, the original cytidine model (C1) was placed at the RANK 25 whereas the phenyl-modified model (C25) was placed at the RANK 1. In this regard, the importance of employing structural modifications for improving the efficiency of ligand interactions with the MTN target were affirmed. Indeed, the carbon groups helped to increase the regions of interactions, in which formations of covalent bonds were also observed for the modified model besides the increased numbers of hydrogen bond and non-hydrogen bond physical interactions. As a consequence, the 4-amino modified models of cytidine were seen to be useful for being considered in the MTN enzyme activity inhibitions.

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