ADME properties prediction of 5-phenyl-5,6-dihydrotetrazolo[1,5-c] quinazolines

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Zaporizhzhia State Medical University

ADME properties prediction of 5-phenyl-5,6-dihydrotetrazolo[1,5-c] quinazolines

Oleksii Antypenko PhD of Pharmacy, Assistant Professor

Department of Organic and Bioorganic Chemistry

Lyudmyla Antypenko PhD of Pharmacy, Associate Professor

Scientific freelancer

Dar'ya Kalnysh 5th Year Student

I Pharmaceutical faculty

Sergiy Kovalenko Professor, Dr. hab., Head

Department of Organic and Bioorganic Chemistry

Ukraine

Аннотация

Прогнозирование свойств ADME ADME-- это четырёхбуквенная аббревиатура, обозначающая всасывание, распределение, метаболизм и выведение фармацевтических соединений.

Термин ADME используется в таких областях, как фармакокинетика и фармакология. Он описывает распределение фармацевтического соединения в организме. Все четыре критерия влияют на уровни лекарственного средства и кинетику воздействия на ткани, а следовательно, на эффективность и фармакологическую активность соединения как лекарственного средства. 5-фенил-5,6-дигидротетразоло[1,5-c] хиназолинов

В связи с недавно предсказанным сродством 13 новых 5-фенил-5,6-дигидротетразоло[1,5-c]-хиназолинов к рибосомальному 50S-белку L2P (2QEX) путем молекулярного докинга, их свойства были рассчитаны на сайте SwissADME, чтобы предсказать их сходство с лекарственными средствами.

Таким образом, вещества 6, 10 и 12 (производные фенилхиназолина) оказались ведущими соединениями среди всех изученных и представляют определенный интерес для дальнейшего изучения антимикробной активности in vitro.

Молекула может быть лекарственным средством, если она может достигать своей цели в организме в достаточной концентрации и остается там в биологически активной форме достаточно долго, чтобы произошли ожидаемые биологические события, и обладает низкой токсичностью. Так называемое правило пяти Липински и др. [1] описывает взаимосвязь между фармакокинетическими и физико-химическими параметрами.

Разработка лекарственных средств все чаще включает в себя оценку всасывания, распределения, метаболизма и выведения (ADME) на ранних стадиях процесса разработки, на этапе, когда рассматриваемых соединений много, но доступ к физическим образцам ограничен. В этом отношении компьютерные модели являются реальной альтернативой экспериментам. Недавно с помощью молекулярного докинга было предсказано сродство 13 новых 5-фенил-5,6-дигидротетразоло[1,5-c]-хиназолинов с эталонным тедизолидом к рибосомальному 50S-белку L2P (2QEX) [2]. Поэтому, прежде чем тестировать эти вещества на антимикробную активность, рекомендуется проверить их биодоступность и профиль токсичности. Веб-инструмент SwissADME SwissADME -- это бесплатный веб-инструмент для оценки фармакокинетики, сходства с лекарственным средством и доступности малых молекул для медицинской химии. Он предоставляет бесплатный доступ к пулу быстрых, но надёжных прогностических моделей физико-химических свойств, фармакокинетики, сходства с лекарственными препаратами и удобства использования лекарственных химикатов. позволяет рассчитать ключевые физико-химические, фармакокинетические, лекарственные и родственные параметры для одной или нескольких молекул [3]. Этот сайт предоставляет бесплатный открытый доступ к быстрым прогностическим моделям, демонстрирующим статистическую значимость, прогностическую силу, интуитивную интерпретацию и простой перевод в молекулярный дизайн.

Цель: Было решено исследовать и сравнить свойства ADME Тедизолида и производных 5-фенил-5,6-дигидротетразоло[1,5-с]хиназолина .

Были рассчитаны физико-химические свойства, также была определена растворимость соединений в воде.

Следовательно, суммируя все вышеприведенные данные, вещества 2, 3, 8, 9, 11, и 13 имели те или иные нарушения. А 4-(5-метил-5,6-дигидротетразоло[1,5-с]-хиназолин-5-ил)фенол (10) был наиболее перспективной молекулой для синтеза и целенаправленного поиска лекарственных средств, наряду с 4-(5,6-дигидротетразоло[1,5-с]хиназолин-5-ил)-бензойной кислотой. кислота (6) и ее 5-метиловый аналог (12), хотя две последние проникают в ГЭБ.

Таким образом, антимикробная активность in vitro планируется в качестве следующего многообещающего этапа исследования.

Ключевые слова: свойства ADME, 5-фенил-5,6-дигидротетразоло[1,5-c]хиназолины, сходство с лекарственными средствами.

Summary

Due to the recent predicted affinity of 13 novel 5-phenyl-5,6-dihydrotetrazolo[1,5-c]- quinazolines to the ribosomal 50S protein L2P (2QEX) by molecular docking, their ADMEproperties were calculated at the site SwissADME to predict their drug-likeness. Hence, substances 6, 10, and 12 appeared to be the leading compounds among all studied ones and are of definite interest for further in vitro antimicrobial activity investigation.

Keywords: ADMEproperties, 5-phenyl-5,6-dihydrotetrazolo[1,5-c]quinazolines, drug-likeness.

Introduction

A molecule could be a drug if it can reach its target in the body in sufficient concentration and remains there in a biologically active form long enough for the expected biological events to occur and has low toxicity.

The so-called Rule- of-five of Lipinski et al. [1] is delineating the relationship between pharmacokinetic and physicochemical parameters.

Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous, but access to the physical samples is limited. In this regard, computer models are a real alternative to experimentation.

Recently, the affinity to the ribosomal 50S protein L2P (2QEX) of 13 novel 5-phenyl-5,6-dihydrotetrazolo[1,5-c]-quinazolines (Fig. 1).with reference Tedizolid was predicted by molecular docking [2].

Fig. 1. Structural formula of Tedizolid as antimicrobial and structural analogue and proposed 5-phenyl-5,6-dihydrotetrazolo[1,5-c]quinazolines

So, before testing these substances for antimicrobial activity, it's advised to check their bioavailability and toxicity profile. And the SwissADME Web tool enables the computation of key physicochemical, pharmacokinetic, drug-like and related parameters for one or multiple molecules [3].

This site gives free open-access and fast predictive models showing statistical significance, predictive power, intuitive interpretation, and straightforward translation to molecular design.

Aim: It was decided to investigate and compare ADME properties of Tedizolid and derivatives of 5-phenyl-5,6-dihydrotetrazolo[1,5-c]quinazoline

Materials and methods

The ergonomic and user-friendly graphical interface for the cost- and login-free Website SwissADME was used to calculate ADME [3]. All descriptors and molecular parameters (physico-chemical properties, lipophilicity, water solubility, pharmacokinetics, drug-likeness) were computed by the protocols explained by SwissADME paper [4].

Tables were formed based on data obtained from the site.

Results and discussion

As a result, firstly, the following physico-chemical properties were calculated, and substances are placed in Table 1 by decreasing of the sum of all their characteristics.

According to the ratio of sp3 hybridized carbons saturation should be at least 0.25 [5], only Tedizolid and substance 13 have the highest value: 0.24. Substances 36 have the lowest number of 0.07.

For size, the molecular weight (MW, calculated by OpenBabel) should be between 150 and 500 g/mol [6].

Table 1

The calculated physico-chemical properties

Number of aromatic heavy atoms is 17 for all.

MW - molecular weight, HA - number of heavy atoms, Csp3 - Fraction Csp3, RB - number of rotatable bonds, HBA - number of H-bond acceptors, HBD - number of H-bond donors, Ref - molar refractivity, TPSA - topological polar surface area.

For polarity, the TPSA should be between 20 and 130 A², considering sulfur and phosphorus as polar atoms [7]. For flexibility, the molecule should not have more than 9 rotatable bonds [6]. For molar refractivity: 40 to 130 [8]. And the characteristics of all test substances are found in the required ranges.

SwissADME gives a Consensus lipophilicity (log P_o/w) value, which is the arithmetic mean of the five predictive values (XLOGP3, atomistic method including corrective factors and knowledge-based library; WLOGP, atomistic method based on the fragmental system; MLOGP, Moriguchi octanol-water partition coefficient based on structural parameters; and Log P calculated by Silicos IT) [4]. And obtained values were placed in Table 2 according to decreasing of their Consensus score.

Table 2

iLOGP relies on Gibbs free energy of solvation calculated by GB/SA in water and n-octanol [9, 10] and its optimal range is from -3.93 to 6.46. Considering MLOGP, it should be < 4.15, and XLOGP3 between - 0.7 and + 5.0 [11, 12]. So, only substances 2 and 9 had violations with MLOGP > 4.15, and XLOGP3 > 3.5, while 8 and 13 had violation only of XLOGP3. While 6, 10, and 12 results were closest to Tedizolid data.

Afterwards water solubility (log S) of compounds was also found (Table 3).

Table 3

The calculated water solubility with Silicos-IT og P decreasing

S - soluble, M - moderately soluble, P - poorly soluble.

Its known, that a drug, meant for parenteral usage, has to be highly soluble in water to deliver a sufficient quantity of active ingredient in the small volume of the pharmaceutical dosage form. А qualitative estimation of the solubility class is given according to the following ESOL model log S scale (insoluble < - 10 < poorly < - 6 < moderately < - 4 < soluble < - 2 < very < 0 < highly soluble) [13]; and the second one is Ali scale (insoluble < -10 poorly < -6, moderately < -4 soluble < -2 very < 0 < highly). The third one of Swiss ADME was developed by Silicos-IT (insoluble < -10 poorly < -6, moderately < -4 soluble < -2 very < 0 < highly) [4]. And for optimal solubility, log S (ESOL) should not exceed 6. Thus, the majority of substances are moderately soluble in water according to this model. And Tedizolid, 6, 10, 12, 7, and 1 are soluble, but 8, 13 and 9 are the less soluble ones. Afterwards, the pharmacokinetic parameters were calculated (Table 4).

pharmacokinetics medicine antimicrobial phenylquinazoline solubility

Table 4

The calculated pharmacokinetics

P-gp - P-glycoprotein 1, BBB - blood-brain barrier,

CYP2D6 - all no, CYP3A4 - only Tedizolidyes, CYP2C19 - only Tedizolid no.

The more negative the log Kp (with Kp in cm/s), the less skin permeant is the molecule [15]. So, 13 has the highest skin permeation with Log Kp = -5.39 cm/s and 8 with -5.61 cm/s, so they could be used in ointments. But their low molecular weight and high degree of lipid solubility favor crossing BBB as the majority of the presented compounds. And, Tedizolid and substances 6, 10 and 12 appeared to be the least skin permeant with no BBB permeation.

The permeability glycoprotein 1 (multidrug resistance protein 1 (MDR1) or ATP- binding cassette sub-family B member 1 (ABCB1), cluster of differentiation 243 (CD243)) is an important protein of the cell membrane that pumps many foreign substances out of cells, for instance from the gastrointestinal wall to the lumen or from the brain [16], and protects the central nervous system (CNS) from xenobiotics [17]. And only half of the substances with Tedizolid are substrates of P-gp. 1 (Table 4).

Although there are different routes of drug administration, oral dosing is highly preferred for the patient's comfort and compliance [18]. And substances 10, 6, 12 are the closest to Tetrazolid by pharmacokinetic properties of passive gastrointestinal absorption. While only 10 is substrate for P-gp. 1. Other substances are predicted to have brain access, which is still can be good in case of treatment of the brain infections. Besides, it's known that a key player in drug elimination through metabolic biotransformation are five major isoforms of cytochrome P450 (CYP) (CYP1A2, CYP2C19, CYP2C9, etc.) [19], to which about 50 to 90% of therapeutic molecules are substrates of. Thus, all investigated substances are inhibitors of CYP2C19, except Tedizolid; all no - for CYP2D6; only Tedizolid for CYP3A4 (Table 4). Substances 6, 10 and 12 are inhibitors of only one cytochrome CYP2C19. For the reference Tedizolid only two cytochromes are also calculated: CYP1A2 and CYP3A4.

Table 5

Drug likeness

The next presented data (Table 5) is drug likeness according to the filters originated from analyses by major pharmaceutical companies aiming to improve the quality of their proprietary chemical collections:

J Lipinski (Pfizer): MW < 500; LogP < 5; HBA < 10; HBD < 5 [1];

J Ghose (Amgen): 160 < MW < 480; -0.4 < WLOGP < 5.6; - 0.4 < MR < 130; 20 < atoms < 70 [20];

J Veber (GSK): Rotatable bonds <1 0; TPSA < 140 [21];

J Egan (Pharmacia): WLOGP < 5.88; TPSA < 131.6 [22];

J Muegge (Bayer): 200 < MW < 600; -2 < XLOGP < 5; TPSA < 150; rings < 7; carbon atoms > 4; heteroatoms > 1; rotatable bonds < 15; HBA<10; HBD<5 [23].

In the result only substances 2 and 9 had violations of the Lipinski rule of lipophilicity: MLOGP > 4.15 (4.21). All other substances comply with all the mentioned authors rules. Moreover, the Abbot Bioavailability Score seeks to predict the probability of a compound to have at least 10% oral bioavailability in rat or measurable Caco-2 permeability [24]. And, obtained results of 0.55-0.56 are considered as sufficiently absorbable via oral route, with substance 6 and 12 having the best values among all.

And SwissADME Bioavailability Radar displays for a rapid appraisal of druglikeness (Fig. 3). Six physicochemical properties are taken into account: lipophilicity, size, polarity, solubility, flexibility, and saturation [5, 25]. It is depicted as a pink area in which the radar plot of the molecule has to fall entirely to be considered drug-like with: lipophilicity: XLOGP3 between -0.7 and+5.0, size: molecular weight between 150 and 500 g/mol, polarity: TPSA between 20 and 130A², solubility: log S not higher than 6, saturation: fraction of carbons in the sp3 hybridization not less than 0.25, and flexibility: no more than 9 rotatable bonds. And it's interesting, that only Tedizolid's and substance's 13 graphs were entirely in the pink area (Fig. 3).

Fig. 3. SwissADME Bioavailability Radar: lipophilicity, size, polarity, solubility, flexibility and saturation

Considering Medical Chemistry parameters calculations (Table 6), according to the SwissADME Synthetic Accessibility Score (SA), that is based primarily on the assumption that the frequency of molecular fragments in 'really' obtainable molecules correlates with the ease of synthesis: 1 (very easy) to 10 (very difficult) (Table 6).

Table 6

Medicinal chemistry data

So, Tedizolid has the most difficult SA among all compounds, still of the moderate level (3.55). All proposed compounds were practically of the same level of SA (3.15-3.38).

Searching for PAINS (pan assay interference compounds, a.k.a. frequent hitters or promiscuous compounds), that are molecules containing substructures showing potent response in assays irrespective of the protein target, there were no alerts for all studied compounds [26].

When analyzing the structural Brenk Alert, consisting of a list of 105 fragments [27] to be putatively toxic, chemically reactive, metabolically unstable, or to bear properties responsible for poor pharmacokinetics, there was only one triple bond detected in the cyano group of substance 11 (Table 6).

Considering lead-likeness, only 2, 9, 13, and 8 had violations of lipophilicity XLOGP3 > 3.5 (3.60, 3.59, 3.78, and 3.53 respectively). Moreover, Tedizolid could be excluded from potential studies, too, if to consider its MW > 350. But it still was found to be a potent antimicrobial agent.

Conclusions

Hence, summing up all above-mentioned data, substances 2, 3, 8, 9, 11, and 13 had violations of some kind. And 4-(5-methyl-5,6- dihydrotetrazolo[1,5-c]-quinazolin-5-yl)phenol (10) was the most promising molecule for synthesis and drug purposeful search, along with 4-(5,6-dihydrotetrazolo[1,5- c]quinazolin-5-yl)-benzoic acid (6) and its 5-methyl analogue 12, although the two latter permeate the BBB. Therefore, the in vitro antimicrobial activity is planned to do as the promising next study stage.

Acknowledgements. The authors are grateful to the Armed Forces of Ukraine for preparing this paper in the safe conditions of Zaporizhzhia.

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