IN-SILICO DESIGN OF FLUTAMIDE ANALOGUES AS ANDROGEN RECEPTOR ANTAGONIST AND MOLECULAR DOCKING STUDIES
HTML Full TextIN-SILICO DESIGN OF FLUTAMIDE ANALOGUES AS ANDROGEN RECEPTOR ANTAGONIST AND MOLECULAR DOCKING STUDIES
Ajay Kumar Gupta, Achal Mishra and Sanmati Kumar Jain *
Drug Discovery and Research Laboratory, Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, Chhattisgarh, India.
ABSTRACT: Androgenic hormones such as testosterone and dihydrotestosterone are essential for the progression of the prostate gland. Overexpression of androgenic receptors is responsible for the proliferation of prostate tumours and androgenic receptors are an essential target in prostate cancer therapy. Flutamide was the first Nonsteroidal androgen receptor antagonist used to treat prostate cancer, but it causes side effects such as hepatotoxicity. This study aims to develop less toxic compounds using a bioisosteric approach by replacing groups such as nitro, trifluoromethyl and aryl of Flutamide drug and to improve pharmacokinetic and toxicity prediction as well as docking studies of newly generated bioisosteres. The Lipinski rule of five was followed. In the docking study, docking scores were obtained in the range of -7.76 to -9.75 Kcal/mol. All ligands docked inside the binding pocket region share a shape that is complementary to the androgen receptor. Among the selected bioisosteres and flutamide, the common amino acid residue 746Val plays a key role in the activity and binding affinity. Based on their QED score, toxicity score, drug likeness, drug score, NR-AR score and binding scores with protein residue, compounds F3, F17, and F39 may be noble antiandrogen agents in the management of prostate cancer.
Keywords: Flutamide, Bioisosteres, ADMET, Prostate Cancer, Molecular docking
INTRODUCTION: Throughout the world, cancer is a major cause of mortality and a leading obstacle to extending life expectancy. Worldwide, approximately 10 million deaths from cancer were reported, compared to 19.3 million cases in 2020. According to estimated data, there are approximately 1.4 million new prostate cancer (PC) patients diagnosed each year and 0.38 million deaths 1.
In men, prostate is a gland which is located in Pelvic region. For normal growth and development of prostate gland, androgenic hormones such as testosterone and dihydrotestosterone (metabolite of testosterone) are required 2-3. Androgenic hormones bind with androgen receptors (AR) and mediate biological effects.
Before puberty, the secretion of androgens are less but in postpuberted male volume of androgens are increased up to ten times, result in continuous growth in prostate glands may lead to benign prostatic hyperplasia (BPH) 4-5. Increased levels of androgens lead to cause proliferation of prostate tumours 6. PC, precious puberty and hair loss are androgen dependent diseases in men, can be treated with antiandrogens.
Antiandrogen agents can be classified into two categories, a) androgen synthetic inhibitors (such as Abiraterone, Seviterone etc.); b) AR antagonist such as steroidal (Cyproterone, Allylestrenol etc.) and non-steroidal (Flutamide, Bicalutamide and Enzalutamide etc.) 7.
Flutamide is chemical propanamide derivative Fig. 1A, used in the treatment of PC and BPH 8. It is an inactive molecule that is activated after going under first pass metabolism (using Cytochrome P450 1A2), resulting in the formation of 2-hydroxyflutamide Fig. 1B 9. Flutamide shows some side effects like drug induced liver injury (DILI) which may lead to liver failure. FDA also reported a warning risk regarding liver nacrosis, jaundice and cholestasis 10-12.
Nitroreduction of Flutamide (formation of N-[4-amino-3-(trifluoromethyl) phenyl] isobutyramide) may cause hepatotoxicity 13. At high doses, flutamide causes some difficulties such as prostatitis, hematuria, hematochezia, anaemia, low libido and elevated methemoglobin in the blood 14.
FIG. 1: STRUCTURE OF FLUTAMIDE, 2-HYDROXY FLUTAMIDE AND BIOISOSTERIC MODIFICATION OF GROUPS (NITRO, TRIFLUOROMETHYL AND ARYL) IN FLUTAMIDE
Bioisosters were compounds that have the same biological activities and are used for modification of potency, efficacy, bioactivitites, pharmacokinetics and toxicological properties 15-16. They can be classified as classical and non-classical bioisosteres.
Classical bioisosters are atoms or molecules having the same valence electrons but share different numbers of atoms. Non-classical bioisosters differ in valance electron but similarity in some important parameters such as liophilicity, pKa, chemical reactivity etc 17-18. For the design of novel and potent molecules chemists or scientists can use rational drug design approaches, among them molecular docking which is used to predict the ligand-protein interaction in three-dimentional mode. Also, docking gives the information about the binding score of the ligand-protein complex may help in lead optimisation 19-20.
The aim of the investigation is to develop a less toxic compound than flutamide through a bioisosteric approach, ADMET properties prediction, drug likeness (DL), drug score (DS) and moleculer docking studies. In Flutamide, three groups such as nitro, trifluromethyl and aryl are modified using the bioisosteric approach is shown in Fig. 1C.
MATERIALS AND METHODS:
Designing of Flutamide Bioisosteres: Flutamide is a pure androgen antagonist used to treat PC. However, in the course of medication, patients were suffering from hepatotoxicity, which led to liver damage. Therefore, it is necessary to modify the flutamide structure in order to reduce toxicity like hepatotoxicity. Various bioisosteres of groups such as nitro, trifluoromethyl, and aryl in Flutamide were generated using the MolOpt online tool. MolOpt, online software used for in-silico design of bioisosteres that uses deep generative models, data mining, and similarity comparisons as bioisosteric transformation rules. A useful feature of MolOpt is that it can navigate historical bioisosteric group space and identify new bioisosteric transformation ideas. The purpose of MolOpt is to assist the medicinal chemist in finding what to make next 21. Types of newly generated analogues of nitro, trifluoromethyl and aryl groups in flutamide are shown in Fig. 2A, 2B and 2C, respectively. The structures of newly generated analogues are shown in Table 1.
FIG. 2: TYPE OF BIOISOSTERES OF NITRO GROUP, TRIFLUOROMETHYL GROUP, ARYL GROUP IN FLUTAMIDE
Pharmacokinetic and Toxicity (ADMET) Properties Prediction: Absorption, distribution, metabolism and excretion and toxicological (ADMET) properties of newly generated analogues of flutamide were calculated using ADMET lab 2.0. It is an integrated online platform with eighty-four quantitative and four qualitative regression models with authentic and extensive predictions of ADMET properties for novel ligands that mimic mammalian ADMET properties tool 22-25.
Drug Likeness and Drug Score Prediction: OSIRIS property explorer (PEO) was employed for DS and DL calculations. PEO includes the processing of all information related to compound synthesis, biological testing, and preclinical development. PEO Online platform with six quantitative and four qualitative regression models with comprehensive prediction of toxicity risk, DL and DS 26.
DL and DS properties determine whether a drug has the physicochemical and biological properties required to be successful and safe for use 27.
Molecular Docking Study: Molecular docking is used in uderstanding molecular biology, determining interactions between targets (macromolecules such as DNA, RNA and Proteins) and small molecules (ligands). Docking softwares is used to understand the recognition of binding affinity, binding score etc 28-29. A molecular docking study of analogues was done using the crystal structure of the androgen receptor (PDB ID: 2AM9) and this study involved a number of steps like preparation of the ligand structure preparation of the protein structures and protein-ligand docking using Argus Lab 4.0 software30-32.
RESULTS AND DISCUSSION:
Bioisosteres of Trifluoromethyl, Nitro and Aryl Groups in Flutamide: As a drug discovery technique, bioisosteric replacement is widely used to improve potency and selectivity, address pharmacokinetic problems and remove unwanted side effects such as toxicity.
MolOpt was used to generate eighty-six, ninety-two and seventy-seven bioisosteres of trifluoromethyl, nitro and aryl groups, in flutamide, respectively. Among these, fifty analogues Table 1 were chosen for further evaluation based on their QED value, DILI score, NR-AR score, DL and DS.
TABLE 1: STRUCTURE AND MOLECULAR PROPERTIES OF THE ANALOGUES
MW; molecular weight, nHA; number of hydrogen bond acceptor, nHD; number of hydrogen bond donor, nRot; number of rotatable bonds, TPSA; topological polar surface area, logP; the logarithm of partition coefficient value, logs; the logarithm of aqueous solubility value.
Screening of Molecular Properties: The molecular properties of the newer analogue were calculated using the ADMETlab2.0 online tool and the results are shown in Table 2. Lipinski's rule of five promotes the bioavailability of the drug candidates. Lipinski's rule of five also predicts the absorption or permeation of the drug candidates 33. The result indicates that all analogues met the acceptance criteria with flutamide as the standard.
TABLE 2: MEDICINAL PROPERTIES OF THE ANALOGUES
Entry no. | QED | Synth | Fsp3 | MCE-18 | Lipinski | Pfizer | GSK | GT |
Aryl Group Bioisosteres | ||||||||
F1 | 0.684 | 2.276 | 0.417 | 13 | Accepted | Accepted | Accepted | Accepted |
F2 | 0.509 | 2.318 | 0.364 | 13 | Accepted | Accepted | Accepted | Accepted |
F3 | 0.684 | 2.324 | 0.417 | 13 | Accepted | Accepted | Accepted | Accepted |
F4 | 0.683 | 2.308 | 0.417 | 13 | Accepted | Accepted | Accepted | Accepted |
F5 | 0.636 | 3.858 | 0.909 | 31 | Accepted | Accepted | Accepted | Accepted |
F6 | 0.684 | 2.162 | 0.417 | 12 | Accepted | Accepted | Accepted | Accepted |
F7 | 0.684 | 2.191 | 0.417 | 12 | Accepted | Accepted | Accepted | Accepted |
F8 | 0.685 | 3.075 | 0.462 | 28 | Accepted | Rejected | Accepted | Accepted |
F9 | 0.684 | 2.407 | 0.417 | 12 | Accepted | Accepted | Accepted | Accepted |
F10 | 0.68 | 2.038 | 0.364 | 12 | Accepted | Accepted | Accepted | Accepted |
F11 | 0.68 | 2.127 | 0.364 | 12 | Accepted | Rejected | Accepted | Accepted |
F12 | 0.68 | 2.123 | 0.364 | 12 | Accepted | Rejected | Accepted | Accepted |
F13 | 0.684 | 2.438 | 0.417 | 12 | Accepted | Rejected | Accepted | Accepted |
F14 | 0.528 | 2.305 | 0.364 | 13 | Accepted | Rejected | Accepted | Accepted |
F15 | 0.659 | 2.4 | 0.364 | 13 | Accepted | Rejected | Accepted | Accepted |
Nitro Group Bioisosteres | ||||||||
F16 | 0.788 | 2.001 | 0.364 | 11 | Accepted | Accepted | Accepted | Accepted |
F17 | 0.848 | 2.179 | 0.333 | 11 | Accepted | Accepted | Accepted | Accepted |
F18 | 0.498 | 2.587 | 0.364 | 11 | Accepted | Accepted | Accepted | Accepted |
F19 | 0.878 | 2.066 | 0.417 | 11 | Accepted | Accepted | Accepted | Accepted |
F20 | 0.878 | 2.029 | 0.462 | 11 | Accepted | Rejected | Accepted | Accepted |
F21 | 0.888 | 2.581 | 0.462 | 24 | Accepted | Accepted | Accepted | Accepted |
F22 | 0.829 | 2.231 | 0.333 | 11 | Accepted | Accepted | Accepted | Accepted |
F23 | 0.799 | 2.042 | 0.333 | 12 | Accepted | Accepted | Accepted | Accepted |
F24 | 0.875 | 2.094 | 0.5 | 12 | Accepted | Rejected | Accepted | Accepted |
F25 | 0.844 | 2.511 | 0.5 | 14 | Accepted | Rejected | Rejected | Accepted |
F26 | 0.823 | 2.219 | 0.357 | 11 | Accepted | Rejected | Rejected | Accepted |
F27 | 0.906 | 1.851 | 0.417 | 11 | Accepted | Rejected | Accepted | Accepted |
F28 | 0.883 | 2.064 | 0.333 | 11 | Accepted | Rejected | Accepted | Accepted |
F29 | 0.686 | 2.031 | 0.385 | 12 | Accepted | Accepted | Accepted | Accepted |
F30 | 0.918 | 2.01 | 0.533 | 35 | Accepted | Rejected | Rejected | Accepted |
F31 | 0.902 | 2.021 | 0.562 | 12 | Accepted | Rejected | Rejected | Accepted |
F32 | 0.891 | 1.958 | 0.333 | 36 | Accepted | Accepted | Accepted | Accepted |
Trifluoromethyl Group Bioisosteres | ||||||||
F33 | 0.616 | 2.039 | 0.364 | 9 | Accepted | Accepted | Accepted | Accepted |
F34 | 0.492 | 2.133 | 0.273 | 9 | Accepted | Accepted | Accepted | Accepted |
F35 | 0.637 | 1.958 | 0.333 | 10 | Accepted | Accepted | Accepted | Accepted |
F36 | 0.667 | 2.091 | 0.5 | 31 | Accepted | Rejected | Accepted | Accepted |
F37 | 0.646 | 2.234 | 0.462 | 12 | Accepted | Accepted | Accepted | Accepted |
F38 | 0.518 | 2.394 | 0.364 | 12 | Accepted | Rejected | Accepted | Accepted |
F39 | 0.634 | 2.587 | 0.417 | 20 | Accepted | Accepted | Accepted | Accepted |
F40 | 0.678 | 2.77 | 0.5 | 44 | Accepted | Accepted | Accepted | Accepted |
F41 | 0.522 | 2.405 | 0.364 | 10 | Accepted | Rejected | Accepted | Accepted |
F42 | 0.639 | 3.626 | 0.65 | 62 | Accepted | Rejected | Rejected | Accepted |
F43 | 0.494 | 2.212 | 0.308 | 9 | Accepted | Rejected | Accepted | Accepted |
F44 | 0.644 | 2.033 | 0.417 | 9 | Accepted | Accepted | Accepted | Accepted |
F45 | 0.67 | 2.103 | 0.533 | 32 | Accepted | Rejected | Rejected | Accepted |
F46 | 0.678 | 1.991 | 0.5 | 31 | Accepted | Accepted | Accepted | Accepted |
F47 | 0.683 | 2 | 0.533 | 32 | Accepted | Accepted | Accepted | Accepted |
F48 | 0.654 | 2.133 | 0.5 | 30 | Accepted | Rejected | Accepted | Accepted |
F49 | 0.683 | 2.281 | 0.533 | 32 | Accepted | Accepted | Accepted | Accepted |
F50 | 0.665 | 2.103 | 0.533 | 32 | Accepted | Accepted | Accepted | Accepted |
Flutamide | 0.68 | 2.07 | 0.364 | 12 | Accepted | Rejected | Accepted | Accepted |
QED; a measure of drug-likeness based on the concept of desirability, Synth; synthetic accessibility score, Fsp3; The number of sp3 hybridized carbons/total carbon count, MCE-18; medicinal chemistry evolution in 2018, GT; golden triangle.
Screening of Medicinal Properties: The medicinal property of analogues are shown in Table 2. QED indicates drug-like properties. The QED value of all analogues has shown > 0.67 with some exceptions such as F2, F5, F14, F15, F18, F33-39, F41-F44, F48 and F50, whereas flutamide has 0.68 which indicates analogues may have drug like properties. All analogues will be easy to synthesise as per synthetic accessibility prediction criteria (< 6). Newer analogues of flutamide were found to be acceptable to Lipinski and the Golden Triangle (GT), indicating good bioavailability. Analogues F3, F17, and F39 have been found to meet Lipinski, Pfizer, GSK, and GT rules, whereas the Pfizer rule for flutamide is rejected.
Screening of Pharmacokinetic (ADME) Properties: Pharmacokinetic properties such as absorption (caco-2, MDCK, HIA), distribution (BBB, PPB, VDss), metabolism (CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4), excretion (CL and T1/2) have been calculated using the ADMET lab2.0 online tool and results are tabulated in Table 3 and 4. Intestinal absorption of analogues was found to be good (absorption score based on the caco-2 score and HIA score). The caco-2 score of analogues was found to be greater than -5.15 which indicates the proper in-vivo drug permeability of analogues.
HIA scores were also found in the range between 0 to 0.3 which indicates oral bioavailability of molecules. The MDCK score of analogues was found to be excellent, indicating high passive permeability. These analogues have moderate to poor BBB permeability, ranging from 0.353 to 0.919. Most of the newer analogues have a predicted plasma protein binding (PPB) score under 90%, which indicates that the high plasma protein binding causes a decrease in the free plasma fraction, which decreases distribution volume and lengthens the half-life of elimination. The volume of distribution (VDs) of all analogues has a good predicted score that is between 0.04-20. From the predicted scores of absorptions and distribution, analogues F3, F6, F17, F19, F37 and F39 and others also have good to moderate permeability effects.
TABLE 3: ABSORPTION AND DISTRIBUTION PROFILE OF THE ANALOGUES
Entry no. | Caco-2 | MDCK | HIA | BBB | PPB (%) | VDss | Fu (%) |
Aryl Group Bioisosteres | |||||||
F1 | -4.414 | Ex | 0.007 | 0.499 | 96.99 | 1.033 | 3.06 |
F2 | -4.437 | Ex | 0.004 | 0.574 | 98.06 | 1.004 | 2.48 |
F3 | -4.448 | Ex | 0.007 | 0.485 | 96.93 | 1.074 | 3.22 |
F4 | -4.348 | Ex | 0.005 | 0.353 | 97.17 | 1.089 | 3.90 |
F5 | -4.582 | Ex | 0.005 | 0.525 | 77.83 | 0.833 | 23.89 |
F6 | -4.458 | Ex | 0.004 | 0.723 | 93.18 | 0.699 | 7.30 |
F7 | -4.444 | Ex | 0.004 | 0.515 | 95.16 | 0.773 | 6.14 |
F8 | -4.362 | Ex | 0.005 | 0.494 | 95.52 | 0.984 | 8.00 |
F9 | -4.383 | Ex | 0.004 | 0.794 | 93.84 | 0.666 | 5.75 |
F10 | -4.333 | Ex | 0.004 | 0.474 | 94.61 | 0.87 | 5.52 |
F11 | -4.344 | Ex | 0.004 | 0.533 | 95.92 | 0.835 | 4.49 |
F12 | -4.435 | Ex | 0.004 | 0.316 | 97.15 | 1.062 | 4.37 |
F13 | -4.479 | Ex | 0.004 | 0.896 | 94.02 | 0.835 | 7.44 |
F14 | -4.336 | Ex | 0.005 | 0.261 | 96.80 | 1.042 | 3.67 |
F15 | -4.332 | Ex | 0.023 | 0.582 | 97.88 | 0.982 | 2.39 |
Nitro Group Bioisosteres | |||||||
F16 | -4.526 | Ex | 0.004 | 0.687 | 85.00 | 1.196 | 15.61 |
F17 | -4.507 | Ex | 0.004 | 0.966 | 90.11 | 1.527 | 10.32 |
F18 | -5.062 | Ex | 0.007 | 0.518 | 97.60 | 5.137 | 3.32 |
F19 | -4.787 | Ex | 0.004 | 0.481 | 62.00 | 2.318 | 35.81 |
F20 | -4.58 | Ex | 0.005 | 0.446 | 95.62 | 3.014 | 4.20 |
F21 | -4.408 | Ex | 0.004 | 0.86 | 87.90 | 0.89 | 14.97 |
F22 | -4.435 | Ex | 0.004 | 0.896 | 88.02 | 1.574 | 10.29 |
F23 | -5.088 | Ex | 0.004 | 0.93 | 88.87 | 1.129 | 11.70 |
F24 | -4.561 | Ex | 0.006 | 0.419 | 96.68 | 3.462 | 3.52 |
F25 | -4.391 | Ex | 0.007 | 0.791 | 93.80 | 3.936 | 6.30 |
F26 | -4.372 | Ex | 0.003 | 0.826 | 97.11 | 1.34 | 2.27 |
F27 | -4.495 | Ex | 0.004 | 0.746 | 94.55 | 3.195 | 5.36 |
F28 | -4.464 | Ex | 0.005 | 0.966 | 92.18 | 0.911 | 6.07 |
F29 | -4.61 | Ex | 0.008 | 0.99 | 89.13 | 0.969 | 24.02 |
F30 | -4.566 | Ex | 0.003 | 0.775 | 95.74 | 2.16 | 2.77 |
F31 | -4.576 | Ex | 0.003 | 0.747 | 96.38 | 2.233 | 2.18 |
F32 | -4.566 | Ex | 0.004 | 0.425 | 91.98 | 1.165 | 10.09 |
Trifluoromethyl Group Bioisosteres | |||||||
F33 | -4.406 | Ex | 0.005 | 0.88 | 73.78 | 0.843 | 28.74 |
F34 | -4.399 | Ex | 0.006 | 0.919 | 84.50 | 1.057 | 14.68 |
F35 | -4.909 | Ex | 0.005 | 0.875 | 80.52 | 0.936 | 23.62 |
F36 | -4.472 | Ex | 0.003 | 0.739 | 96.58 | 0.806 | 2.94 |
F37 | -4.326 | Ex | 0.01 | 0.731 | 80.12 | 0.909 | 23.43 |
F38 | -5.52 | Ex | 0.004 | 0.872 | 98.18 | 1.28 | 1.59 |
F39 | -4.404 | Ex | 0.005 | 0.781 | 76.36 | 0.83 | 26.13 |
F40 | -4.485 | Ex | 0.003 | 0.642 | 92.80 | 0.851 | 7.98 |
F41 | -4.79 | Ex | 0.004 | 0.811 | 96.53 | 1.263 | 3.62 |
F42 | -4.683 | Ex | 0.004 | 0.69 | 96.28 | 1.015 | 1.15 |
F43 | -4.249 | Ex | 0.004 | 0.557 | 96.00 | 0.986 | 2.68 |
F44 | -4.333 | Ex | 0.004 | 0.881 | 74.80 | 0.927 | 23.54 |
F45 | -4.489 | Ex | 0.003 | 0.699 | 97.30 | 0.842 | 2.09 |
F46 | -4.42 | Ex | 0.004 | 0.824 | 94.79 | 0.924 | 4.86 |
F47 | -4.441 | Ex | 0.004 | 0.806 | 95.96 | 0.915 | 3.98 |
F48 | -4.466 | Ex | 0.003 | 0.735 | 95.56 | 0.664 | 2.70 |
F49 | -4.471 | Ex | 0.002 | 0.598 | 93.96 | 0.756 | 6.25 |
F50 | -4.375 | Ex | 0.003 | 0.779 | 96.90 | 0.728 | 2.63 |
Flutamide | -4.346 | Ex | 0.004 | 0.58 | 95.62 | 0.832 | 4.59 |
Caco-2; the human colon adenocarcinoma cell lines, MDCK; Madin−Darby canine kidney cells, HIA; human intestinal absorption, PPB; plasma protein binding, BBB; blood–brain barrier, VD; volume distribution, Fu; the fraction unbound in plasms, Ex; Excellent.
Cytochrome P450 (CYT P450) is involved in the digestion of drugs, lipids, steroidal components, and carcinogens. Analogues may be substrate or inhibitors. If they are substrates for the enzyme CYT P450 result in the metabolism takes place with molecules, on the other hand, if they inhibit the enzyme, it will be inactive in metabolism. Analogue F3 was an inhibitor while analogues F17 and F34 were substrates for all five isozymes. Approximately 50% of analogues have an excellent clearance score, indicating a low risk of toxicity. Among them analogue F3 and F29 have excellent clearance scores (≥ 5) and analogue F17 has a moderate clearance score (≤ 5). T1/2 of analogues F3 and F39 were found under the range (0 to 0.3) which indicates excellent clearance from the body.
TABLE 4: METABOLISM AND EXCRETION PROFILE OF THE ANALOGUES
Entry no. | CYP1A2 | CYP2C19 | CYP2C9 | CYP2D6 | CYP3A4 | CL | T1/2 |
Aryl Group Bioisosteres | |||||||
F1 | - | - | - | + | - | 4.349 | 0.3 |
F2 | - | - | + | - | + | 4.579 | 0.495 |
F3 | - | - | - | - | - | 6.774 | 0.283 |
F4 | + | + | - | + | + | 3.408 | 0.419 |
F5 | + | + | - | + | + | 6.446 | 0.4 |
F6 | - | - | + | + | - | 5.882 | 0.297 |
F7 | - | + | - | + | - | 5.217 | 0.454 |
F8 | + | + | + | + | + | 4.821 | 0.345 |
F9 | - | - | + | + | - | 6.586 | 0.642 |
F10 | + | + | + | + | + | 3.795 | 0.308 |
F11 | + | + | + | + | + | 4.608 | 0.224 |
F12 | + | + | - | - | - | 4.096 | 0.259 |
F13 | - | - | - | + | + | 6.624 | 0.246 |
F14 | + | - | + | + | + | 3.016 | 0.232 |
F15 | + | - | + | + | + | 1.226 | 0.207 |
Nitro Group Bioisosteres | |||||||
F16 | + | + | - | + | + | 7.88 | 0.192 |
F17 | - | + | + | + | + | 2.634 | 0.252 |
F18 | + | + | + | + | + | 0.783 | 0.321 |
F19 | - | + | + | + | + | 8.645 | 0.547 |
F20 | + | + | + | + | + | 7.332 | 0.295 |
F21 | + | + | + | + | + | 4.611 | 0.37 |
F22 | + | + | + | + | + | 4.077 | 0.366 |
F23 | + | + | + | + | + | 5.808 | 0.216 |
F24 | + | + | - | + | + | 5.312 | 0.17 |
F25 | + | + | - | + | + | 2.284 | 0.198 |
F26 | + | - | + | + | - | 7.543 | 0.169 |
F27 | + | + | + | + | + | 9.662 | 0.322 |
F28 | + | + | - | + | + | 8.524 | 0.297 |
F29 | - | + | + | - | - | 2.998 | 0.411 |
F30 | + | + | - | + | + | 5.648 | 0.095 |
F31 | + | + | - | + | - | 5.31 | 0.076 |
F32 | + | + | - | + | + | 1.355 | 0.691 |
Trifluoromethyl Group Bioisosteres | |||||||
F33 | + | + | + | + | + | 6.474 | 0.882 |
F34 | - | + | + | + | + | 2.213 | 0.58 |
F35 | - | - | + | + | + | 8.056 | 0.696 |
F36 | + | - | + | + | + | 1.385 | 0.234 |
F37 | + | + | + | + | + | 4.194 | 0.689 |
F38 | + | + | + | + | + | 3.464 | 0.316 |
F39 | + | + | + | + | + | 4.76 | 0.762 |
F40 | + | + | + | + | + | 4.775 | 0.429 |
F41 | + | + | + | + | + | 3.047 | 0.485 |
F42 | + | - | + | + | - | 1.74 | 0.07 |
F43 | + | - | + | + | - | 5.556 | 0.604 |
F44 | + | + | + | + | + | 5.252 | 0.615 |
F45 | + | - | + | + | - | 1.436 | 0.2 |
F46 | + | - | - | + | - | 4.765 | 0.364 |
F47 | + | - | - | - | - | 4.396 | 0.299 |
F48 | + | - | + | + | - | 3.098 | 0.272 |
F49 | + | + | + | - | + | 5.391 | 0.341 |
F50 | + | - | + | - | - | 3.617 | 0.24 |
Flutamide | + | - | + | + | + | 4.681 | 0.237 |
(-); indicates inhibitor, (+); indicates substrate of human cytochrome P450 (five isozymes-1A2, 3A4, 2C9, 2C19 and 2D6), CL; the clearance of a drug, T1/2; the half-life of a drug.
Screening of Toxicity Profile: Toxicity parameters of newer analogues such as Drug Induced Liver Injury (DILI), mutagenicity (Ames), androgen receptor-a nuclear hormone receptor (NR-AR) were calculated using ADMET lab 2.0 online tool and their results are shown in Table 5. The DILI scores for analogues F6, F17, F19, F25, F34, F35, F37 and F42 are moderate (0.3 to 0.7). However, analogues F7, F37 and F41 are safe, while flutamide has high liver toxicity (0.858). Studies have shown that analogues such as F17, F34, F38, F41 do not cause human hepatotoxicity (H-HT) as compared to Flutamide (0.578). The mutagenicity of analogues such as F1, F2, F3, F5, F7, F8, F17, F19, F20, F21, F23, F24, F25, F26 and F42 was predicted to be safer than flutamide (0.498), indicating that the analogues could not cause mutagenesis. The rat oral acute toxicity (ROA) method is used to determine acute toxicity in rats and mice, which is an important safety profile for drug candidates. Based on the outcome of ROA, analogues are as safe as flutamide, except for F19. The carcinogenicity of chemicals is a serious issue because of their powerful effects on wellness and because they can damage the genome or disrupt cellular metabolism. According to the results of carcinogenicity scores, analogues such as F17, F19, F20, F21, F22, F23, F24, F25, F33, F34, F35, F38, F39, F41 and F42 were found to have a safe predictive value. NR-AR plays a vital role in AR-dependent PC, as well as other androgen-related diseases. In more than 75% of cases, analogues bind to the NR-AR, inhibiting the activity of the Androgen receptor. In general, analogues F1-F4, F6, F7, F9, F23, F36, F38 and F39 were found to have more than 0.8 scores.
TABLE 5: TOXICITY PROFILE OF THE ANALOGUES
Entry no. | H-HT | DILI | Ames | ROA | Carc. | NR-AR | NR-AR-LBD |
Aryl Group Bioisosteres | |||||||
F1 | 0.724 | 0.572 | 0.196 | 0.159 | 0.74 | 0.847 | 0.095 |
F2 | 0.552 | 0.671 | 0.177 | 0.271 | 0.737 | 0.807 | 0.178 |
F3 | 0.708 | 0.58 | 0.205 | 0.199 | 0.741 | 0.85 | 0.103 |
F4 | 0.736 | 0.654 | 0.488 | 0.238 | 0.844 | 0.849 | 0.017 |
F5 | 0.919 | 0.622 | 0.008 | 0.041 | 0.882 | 0.089 | 0.002 |
F6 | 0.485 | 0.43 | 0.458 | 0.115 | 0.725 | 0.845 | 0.009 |
F7 | 0.485 | 0.185 | 0.29 | 0.108 | 0.588 | 0.826 | 0.011 |
F8 | 0.338 | 0.675 | 0.013 | 0.06 | 0.751 | 0.011 | 0.003 |
F9 | 0.379 | 0.609 | 0.457 | 0.128 | 0.52 | 0.816 | 0.007 |
F10 | 0.662 | 0.87 | 0.624 | 0.123 | 0.793 | 0.861 | 0.032 |
F11 | 0.626 | 0.874 | 0.616 | 0.063 | 0.788 | 0.862 | 0.027 |
F12 | 0.62 | 0.729 | 0.498 | 0.058 | 0.753 | 0.844 | 0.048 |
F13 | 0.527 | 0.714 | 0.216 | 0.069 | 0.682 | 0.803 | 0.007 |
F14 | 0.749 | 0.889 | 0.5 | 0.158 | 0.731 | 0.874 | 0.075 |
F15 | 0.405 | 0.934 | 0.305 | 0.118 | 0.683 | 0.878 | 0.12 |
Nitro Group Bioisosteres | |||||||
F16 | 0.596 | 0.696 | 0.524 | 0.234 | 0.357 | 0.749 | 0.006 |
F17 | 0.258 | 0.347 | 0.204 | 0.084 | 0.183 | 0.732 | 0.006 |
F18 | 0.454 | 0.691 | 0.993 | 0.079 | 0.965 | 0.001 | 0.013 |
F19 | 0.481 | 0.384 | 0.039 | 0.868 | 0.231 | 0.795 | 0.004 |
F20 | 0.82 | 0.456 | 0.129 | 0.243 | 0.123 | 0.619 | 0.003 |
F21 | 0.654 | 0.533 | 0.116 | 0.156 | 0.117 | 0.762 | 0.003 |
F22 | 0.416 | 0.688 | 0.391 | 0.127 | 0.111 | 0.742 | 0.006 |
F23 | 0.352 | 0.95 | 0.284 | 0.105 | 0.147 | 0.847 | 0.003 |
F24 | 0.65 | 0.488 | 0.04 | 0.153 | 0.153 | 0.191 | 0.002 |
F25 | 0.33 | 0.399 | 0.012 | 0.01 | 0.111 | 0.61 | 0.002 |
F26 | 0.426 | 0.522 | 0.063 | 0.113 | 0.553 | 0.572 | 0.004 |
F27 | 0.263 | 0.839 | 0.023 | 0.139 | 0.285 | 0.786 | 0.004 |
F28 | 0.913 | 0.896 | 0.105 | 0.17 | 0.391 | 0.836 | 0.037 |
F29 | 0.049 | 0.733 | 0.042 | 0.138 | 0.304 | 0.789 | 0.007 |
F30 | 0.848 | 0.78 | 0.121 | 0.535 | 0.329 | 0.745 | 0.005 |
F31 | 0.84 | 0.815 | 0.114 | 0.512 | 0.293 | 0.722 | 0.005 |
F32 | 0.218 | 0.973 | 0.017 | 0.339 | 0.082 | 0.852 | 0.004 |
Trifluoromethyl Group Bioisosteres | |||||||
F33 | 0.575 | 0.419 | 0.832 | 0.046 | 0.262 | 0.635 | 0.021 |
F34 | 0.156 | 0.39 | 0.964 | 0.024 | 0.109 | 0.36 | 0.205 |
F35 | 0.58 | 0.4 | 0.918 | 0.054 | 0.079 | 0.035 | 0.005 |
F36 | 0.48 | 0.839 | 0.884 | 0.329 | 0.534 | 0.828 | 0.008 |
F37 | 0.598 | 0.395 | 0.629 | 0.037 | 0.378 | 0.709 | 0.005 |
F38 | 0.109 | 0.5 | 0.978 | 0.018 | 0.147 | 0.815 | 0.016 |
F39 | 0.589 | 0.225 | 0.698 | 0.045 | 0.136 | 0.8 | 0.013 |
F40 | 0.585 | 0.535 | 0.944 | 0.17 | 0.428 | 0.756 | 0.016 |
F41 | 0.066 | 0.247 | 0.96 | 0.029 | 0.112 | 0.659 | 0.019 |
F42 | 0.338 | 0.374 | 0.143 | 0.317 | 0.55 | 0.382 | 0.006 |
F43 | 0.316 | 0.455 | 0.93 | 0.049 | 0.214 | 0.719 | 0.017 |
F44 | 0.659 | 0.778 | 0.913 | 0.045 | 0.268 | 0.744 | 0.035 |
F45 | 0.441 | 0.853 | 0.885 | 0.392 | 0.599 | 0.838 | 0.006 |
F46 | 0.461 | 0.921 | 0.97 | 0.168 | 0.369 | 0.825 | 0.017 |
F47 | 0.41 | 0.925 | 0.969 | 0.166 | 0.389 | 0.842 | 0.013 |
F48 | 0.495 | 0.827 | 0.931 | 0.078 | 0.489 | 0.812 | 0.005 |
F49 | 0.489 | 0.694 | 0.912 | 0.669 | 0.531 | 0.733 | 0.008 |
F50 | 0.506 | 0.846 | 0.937 | 0.123 | 0.665 | 0.868 | 0.017 |
Flutamide | 0.578 | 0.858 | 0.498 | 0.067 | 0.786 | 0.862 | 0.018 |
H-HT; the human hepatotoxicity, DILI; drug-induced liver injury, Ames; Test for mutagenicity, ROA; rat oral acute toxicity, NR-AR; androgen receptor - a nuclear hormone receptor, NR-AR-LBD; molecule bind with LBD of androgen receptor, Carc.; carcinogenicity.
Screening of DL and DS: Parameters like mutagenicity, tumorigenicity, irritant, reproductive, DL, and DS have been calculated using PEO. The results of DL and DS are shown in Table 6. Around 75% of analogues showed good DL scores and all newer analogues showed higher DS than flutamide. The DL score was -6.59 for analogue F19 followed by ligand F24 with a DL score of -6.14. The maximum DS was found 0.44 for analogue F2 and F5 followed by ligands F6, F7, F9 and F10 with the DL score of 0.43.
TABLE 6: DRUG LIKENESS AND DRUG SCORE OF ANALOGUES
Entry no. | Toxicity Risk | DL | DS | |||
M | T | I | R | |||
Aryl Group Bioisosteres | ||||||
F1 | G | G | G | G | -10.19 | 0.42 |
F2 | G | G | G | G | -11.50 | 0.44 |
F3 | G | G | G | G | -10.66 | 0.42 |
F4 | G | G | G | G | -11.23 | 0.40 |
F5 | G | G | G | G | -10.84 | 0.44 |
F6 | G | G | G | G | -12.02 | 0.43 |
F7 | G | G | G | G | -21.78 | 0.43 |
F8 | G | G | G | G | -11.16 | 0.41 |
F9 | G | G | G | G | -12.89 | 0.43 |
F10 | G | G | G | G | -12.4 | 0.43 |
F11 | R | O | G | O | -14.93 | 0.16 |
F12 | G | G | G | G | -22.34 | 0.43 |
F13 | R | O | G | O | -11.53 | 0.14 |
F14 | G | G | G | G | -12.76 | 0.41 |
F15 | G | G | G | G | -14.55 | 0.36 |
Nitro Group Bioisosteres | ||||||
F16 | R | O | G | O | -9.74 | 0.17 |
F17 | R | O | G | O | -8.65 | 0.16 |
F18 | R | O | G | O | -8.45 | 0.15 |
F19 | R | O | G | O | -6.59 | 0.17 |
F20 | R | O | G | O | -7.01 | 0.16 |
F21 | R | O | G | O | -8.69 | 0.17 |
F22 | R | O | G | O | -7.32 | 0.16 |
F23 | R | O | G | O | -6.8 | 0.16 |
F24 | R | O | G | O | -6.14 | 0.15 |
F25 | R | O | R | O | -52.49 | 0.08 |
F26 | R | O | G | O | -9.24 | 0.14 |
F27 | R | O | G | O | -5.93 | 0.17 |
F28 | R | O | G | O | -10.78 | 0.16 |
F29 | R | O | G | O | -5.94 | 0.16 |
F30 | R | O | G | O | -5.59 | 0.15 |
F31 | R | O | G | O | -7.1 | 0.14 |
F32 | R | O | G | O | -8.92 | 0.17 |
Trifluoromethyl Group Bioisosteres | ||||||
F33 | R | O | G | O | -6.86 | 0.18 |
F34 | R | O | G | O | -9.02 | 0.17 |
F35 | R | O | G | O | -5.32 | 0.18 |
F36 | R | O | G | O | -7.22 | 0.15 |
F37 | R | O | G | O | -7.81 | 0.17 |
F38 | R | O | R | R | -6.87 | 0.05 |
F39 | R | O | G | O | -8.02 | 0.18 |
F40 | R | O | G | O | -8.03 | 0.17 |
F41 | R | R | R | R | -6.6 | 0.05 |
F42 | R | O | G | O | -6.4 | 0.11 |
F43 | R | O | G | O | -9.6 | 0.16 |
F44 | R | O | G | O | -6.88 | 0.18 |
F45 | R | O | G | O | -8.94 | 0.15 |
F46 | R | O | G | O | -4.31 | 0.17 |
F47 | R | O | G | O | -5.82 | 0.16 |
F48 | R | O | G | O | -5.87 | 0.16 |
F49 | R | O | G | O | -9.87 | 0.16 |
F50 | R | O | G | O | -11.67 | 0.15 |
Flutamide | R | O | G | O | -12.9 | 0.16 |
M; mutagenic, T; Tumorigenic, I; irritant, R; reproductive, G; no toxicity risk, O; toxicity risk, R; high toxicity risk, DL; drug likeness, DS; drug score.
Molecular Docking Study of Flutamide Analogues: The structures of all ligands (Table 1) were drawn in 2D, converted into 3D, and saved as .mol/PDB file. In order to optimise the ligands for docking, they were first optimised. All the ligands we reanalysed for their interaction with proteins through docking scores. A molecular docking score identifies ligands that interact with orientation, as seen with the androgen receptor. A 3D and 2D interaction between ligands and androgen receptors is shown in Fig. 3 and 4, respectively. The ligands showed good docking poses. Table 7 displays the log values of the ligands as well as the protein-ligand interaction scores (total score values) found during docking (the docked postures obtained through visualisation). Docking poses were identified for the ligands with the target protein. Docking poses must demonstrate how the ligand fits into the binding region of the protein.
FIG. 3: 3D DOCKING POSES OF COMPOUND F3, F17, F39 AND FLUTAMIDE
FIG. 4: 2D DOCKING POSES OF COMPOUND F3, F17, F39 AND FLUTAMIDE
Based on the docked conformations of the androgen receptor complex, intermolecular docking simulations were conducted and energy values calculated. Most of the ligands had good binding scores with 2AM9. The interaction was measured by the binding energy of the best ligand pose measured in kcal/mol. The binding poses and their energy are listed in Table 7. The obtained docking scores are between -7.76 to -9.75Å. All the ligands docked within the binding pocket region suggest their shape complements with the androgen receptor. The 3-dimentional presentation of the docking pose of ligand molecules like F3, F17, F39, and Flutamide with androgen receptors is shown in Fig. 3. Compared to flutamide as a standard, most compounds have very good docking scores. Ligands like F3, F17, F19, and F37 showed higher docking scores and multiple docking poses. In ligand F1, multiple interactions were observed, including 845ARG, 858GLN, and 845ARG at distances of 2.99Å, 2.55Å, and 2.98Å, respectively. Ligand F6 had multiple interactions with amino acid residues such as 752ARG at different distances of 2.83Å, 2.32Å, and 2.99Å. There was no interaction between Ligand F7 and any amino acid residue. Ligand F9 shows the interaction with the 746VAL residue of amino acid at a distance of 2.74Å. Ligand F19 interacted with 746PHE and 752ARG residue of amino acid at distance 2.99Å and 2.83Å, respectively. In addition, Ligand F37 has interacted with various amino acid residues such as 752ARG, 708GLY, and 704LEU at a distance of 2.25Å, 2.52Å, and 2.89Å, respectively. Furthermore, ligands F3, F17, and F39 were found to show interaction with the same amino acid residue 746VAL at a distance of 2.99Å, 2.13Å and 2.31Å, respectively, as shown in Table 7. These compounds might be powerful androgen receptor inhibitors, based on the results. In this study, it has been observed that some compounds show common amino acid residue (746VAL) interactions with ligands which have a significant role in binding and biological activity. 746Val protein amino acid residue and flutamide interacted with carbon-hydrogen residue which is also shown in the literature 34. 746VAL might account for this anti-tumour activity. An important outcome of this study may result in the design of novel androgen receptor antagonists along with docking analysis.
TABLE 7: DOCKING SCORE OF THE ANALOGUES
Entry no. | Docking score (Kcal/mol) | Amino acids interaction |
Aryl Group Bioisosteres | ||
F1 | -7.76024 | 1500N-854ARG,2.99A, 1543N-858GLN,2.55A, 1500N-854ARG,2.93A, 1543N-858GLN,2.49A, 1497N-854ARG,2.33A |
F3 | -7.88016 | 1180N-746VAL,2.99A |
F4 | -9.55183 | 1826S-784CYS,2.53A |
F6 | -8.74 | 1284N-752ARG, 2.83A, 1284N-752ARG, 2.32A, 1283N-752ARG, 2.99A |
F7 | - | No Hydrogen Bonds |
F9 | -9.052 | 1284N-752ARG, 2.74A |
Nitro Group Bioisosteres | ||
F17 | -8.75 | 1180N-746VAL, 2.131A |
F19 | -9.48 | 1482O-764PHE, 2.99A, 1284N-752ARG, 2.83A |
F21 | -9.71 | 1166O-745MET, 2.900A |
Trifluoromethyl Group Bioisosteres | ||
F37 | -9.01 | 1284N-752ARG, 2.25A, 559N-708GLY, 2.52A, 495O-704LEU, 2.89A |
F38 | -9.75 | 1812N-783GLN,2.99A, 3494N-883LYS, 2.59A |
F39 | -8.81937 | 1180N-746VAL,2.31A |
F40 | -7.90854 | 1740N-779ARG,2.56A, 1740N-779ARG,2.99A |
Flutamide | -8.26474 | 1180N-746 VAL,2.25A |
CONCLUSION: Flutamide is one of the antiandrogen drugs used in the treatment of PC. Hepatotoxicity is a major side effect, which is why drugs are pulled from the market. Flutamide was structurally modified by using a bioisosteric approach to get less toxic compounds than flutamide. The in-silico design of drugs is a promising method for developing antiandrogen drugs. In the design of newer analogues of flutamide, a bioisosteric approach was used. As part of the investigation, ADMET lab 2.0 and PEO were used to calculate ADMET properties, DL and DS. For the docking study, Argus Lab 4.0.1 was used to confirm the best docking score by interaction between ligand and protein. A docking study of F3, F7, F17, F19, F37, and F39 ligands demonstrated that these ligands had better binding characteristics with the androgen receptor model in comparison to the other ligands. The docking study reflects that the ligands interact with the androgen receptor, which is evident by the docking scores. Ligands F3, F17, F39 and flutamide had similar interactions (746Val amino acid residue). The common amino acid residue 746Val plays a crucial role in the activity and binding affinity of the selected compounds. The data obtained from ADMET properties prediction, DL, DS, and docking studies of ligands, compounds F3, F17, and F39 could be promising drugs in the management of PC.
ACKNOWLEDGMENTS: The authors wish to thank the Head, Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG) for providing required facilities to perform the research work.
CONFLICTS OF INTEREST: The authors declare that they have no known financial conflicts of interest.
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Gupta AK, Mishra A and Jain SK: In-silico design of flutamide analogues as androgen receptor antagonist and molecular docking studies. Int J Pharm Sci & Res 2023; 14(12): 5785-01. doi: 10.13040/IJPSR.0975-8232.14(12).5785-01.
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Article Information
26
5785-5801
3196 KB
209
English
IJPSR
Ajay Kumar Gupta, Achal Mishra and Sanmati Kumar Jain *
Drug Discovery and Research Laboratory, Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, Chhattisgarh, India.
sanmatijain72@yahoo.co.in
20 April 2023
04 July 2023
28 July 2023
10.13040/IJPSR.0975-8232.14(12).5785-01
01 December 2023