Psoriasis Vrs Cassia Fistula: In-Silico Study

Saudi Journal of Medicine Abbreviated Key Title: Saudi J Med ISSN 2518-3389 (Print) |ISSN 2518-3397 (Online) Scholars Middle East Publishers, Dubai, United Arab Emirates Journal homepage: https://saudijournals.com Original Research Article Psoriasis Vrs Cassia Fistula: In-Silico Study Mr. Chandra Sekhar Tripathy1, Dr. Anil Kumar2, Prof. Ghassem Habibi Bibalani3, Dr. Santosh Kumar Behera4, Santanu Kumar Budhia5, Dr. P K Mohanta6, Easter Khura7, Dr. Asadollah Asadi8, Dr. Arash Abdolmaleki9, Prof. Muhammad Akram10, Dr. Debasish Mishra11, Deepak Bhattacharya12* 1 M. Sc., Regional Medical Research Centre, Bhubaneswar, Odisha, India, Principal Scientist & Head, Division of Design of Experiments I.C.A.R-I.A.S.R.I., Library Avenue, New Delhi, India, PIN- 110012 3 Ph.D, Department of Natural Resources, Shabestar Branch, Islamic Azad University, Shabestar, Iran 4 Ph.D., Scientist Grade II, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India 5 BA; Traditional Ayurvedacharya, Nagharen Temple Rd, Baabajee Padaa, Balangir, Odisha, India 6 MD (Ay), Govt Drug Inspector; Registrar Ay Council; Principal, IGMMC & amp; Hospital, H-2/58, SS Enclave, Khandagiri, Bhubaneswar-751030, Odisha, India 7 M Sc (nursing), Vice Principal, School of Nursing, Raxaul, Bihar, India – 845305 8 Associate Professor, Department of Biology, University of Mohaghegh Ardabili, Iran 9 Assistant Professor, Animal Physiology, University of Mohaghegh Ardabili, Faculty of Advanced Technologies, Department of Biology, Ardabil Province, Ardabil, Daneshgah St, Iran 10 BEMS, M.Phil, Ph.D, Chairperson, Dept. of Eastern Medicine, Government Collage University, Faisalabad, Pakistan 11 MBBS, Director – Govt Blood Bank – Apex, Capital Hospital, Bhubaneswar, Odisa, India – 751009 12 Ph.D., Policy, Nursing, At Fight-Cancer at Home, Medicinal Toxicology & QC, At : Sri Radha Krishna RaasMandir, KedarGouri Road, Bhubaneswar–751002,Odisa, India. 2 DOI: 10.36348/sjm.2022.v07i03.005 | Received: 30.11.2021 | Accepted: 03.01.2022 | Published: 22.03.2022 *Corresponding Author: Deepak Bhattacharya, Ph.D Policy, Nursing, At Fight-Cancer at Home, Medicinal Toxicology & QC, At : Sri Radha Krishna RaasMandir, Kedar Gouri Road, Bhubaneswar–751002,Odisa, India. Email: fightcancermetastasisathome@gmail.com Abstract Psoriasis is a skin disease. It is rare growing disease around the world. Here in this investigation we have targeted a protein namely TRPV3 (Transient receptor potential cation channel, subfamily III) ion channel for the study of psoriasis, which is important factor of psoriasis. The medicinal plant namely Cassia fistula is selected for the in silico investigation. 39 phyto compounds as reported in various research papers are taken for study. Out of 39 phytochemicals, Chrysophanol compound showed highest binding affinity of -7.58kcal/mol having 3 conventional Hydrogen bonds with TRPV3 protein and is found to be a better natural compound as compared to other reported drugs generally used to for the psoriasis. This investigation will lead to more and better findings leading to drug discovery & use as functional food. Keywords: Psoriasis; TRPV3 ion channel; Cassia fistula; Molecular docking; in silico study. Copyright © 2021 The Author(s): This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY-NC 4.0) which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited. INTRODUCTION Skin is the largest organ. And the one that also is connected to the (i) vital physiological process (ii) deep brain (iii) entire neuronal circuit (iv) experiences maximum weathering 24 x 7. Psoriasis and its variants are a chronic immune-mediated inflammatory malady of the skin. Initial variant can change during malady insitu period with or without a nexus to small bone joints & tendons viz., psoriatic arthritis (metabolic pathways). Is acutely debilitating; disconcerting and inflicts deep psychological stress 24 x 7. It can happen to anyone, anytime. Are non-communicable; not vectorable; yet chance filial. Thus far every variant have failed curative efforts- century scale [R-1]. Various genes and systemic factors are involved. Phyto; hormone; aroma; cholinergic; carcinogens; anti-tissue; anti-neoplastic (solid & liquid tumors\cancers); target; monoclonal Citation: Mr. Chandra Sekhar Tripathy, Dr. Anil Kumar, Prof. Ghassem Habibi Bibalani, Dr. Santosh Kumar Behera, Santanu Kumar Budhia, Dr. P K Mohanta, Easter Khura, Dr. Asadollah Asadi, Dr. Arash Abdolmaleki, Prof. Muhammad Akram, Dr. Debasish Mishra, Deepak Bhattacharya (2022). Psoriasis Vrs Cassia Fistula: In-Silico Study. Saudi J Med, 7(3): 148-158. 148 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 anti-body; target; repurposed; etc., therapies (every school) have all been tried with non yielding any (even near assured) drug dose repeatable results. Too many have indicated unacceptable contradictions and individual specific biphasic character post initial few dose of positive indication. Non leave identical traces of metabolic; drug mechanics and kinematics (unacceptable). Animal models are unethical and moreover have proved as idiotic. This has posited psoriasis as an enigma and its clinical management as pharmacist’s & physician’s dilemma. There is no therapy [R-2]. Due such historical track of failure in anti-psoriasis drug discovery it has become very expensive; frown-full with disapprovals from the support frame work. Thus there is a need for a paradigm shift in (neo) drug source\starting material i.e., prescreening viz., in-silico study. We have selected the economic and abundant Cassia fistula belonging to kingdom plantae, family Fabacae, genus Cassia and spp., Fistula [ R-3]; it is more known as an ornamental\ promenade tree. In Ayurveda this genus is described to be useful in skin diseases, cardiac disorders, tuberculosis, liver, leukemia; diabetes; constipation related problems and in mono and poly herbal modern formulations. It is abundantly available in the entire tropo-equatorial belts worldwide. However, it has not been used in the caption domain pre to this communication. Here we report the docking specificity of its natural compounds with the principal (anthropogenic) gene that is responsible for the malady psoriasis. This is an original; 1st time and yet is only an indicative work as assistance to others. MATERIALS& METHODS Gene selection for the study The gene ‘Transient receptor potential cation channel, subfamily III’ (TRPV-3) has been selected as it is the most involvedin thepatho-physiology of all psoriasis variants & stages [R-4]. Phyto-Sources Herbs are veritable source for drug discovery. There are a many different types of medicinal plants in nature which all on psoriasis have varying effect between them with non-reproducing therapeutic efficacy. They also fall acutely short of efficacy as compared to conventional drugs. While such conventional treatments have remained limited to steroids cum toxic moieties; carcinogens; functional food and changes in life style. Herbal combinations thus far have also not provide any panacea. Moreover, all natural sources necessarily are not nontoxic. Nontoxic therapy is the call of present times. Therefore, there is a crying need & opportunity. In this communication we have selected (almost all) the known natural compounds of the treeCassia fistula Linn. Fabaceace(Fig-1 (a) and (b)). It is non-toxic [Ref -5]; not noted in Classical Ayurveda [R-6, 7]; nor in Sino schools [R-8];. However, Cassia angustifoliaVahl is mentioned in the Ayurvedic Pharmacopeia & in the official formularies, respectively [R-9; 10]. Whereas, post independent Indian Scientific Compendiums of medicinal plants of india deals with fistula abundantly [R-11, 12 and 13]. None of the works indicate any usage vis-à-vis Psoriasis. Fig-1(a): Shows Cassia Fistula the summer flowering tree with fruits as on 1-11-2021., Bhubaneswar, India and (b) shows the bark on its trunk. It contains Chrysophanol the most sans Oxyanthraquinone. PHYTOCHMICALS OF Cassia fistula Cassia fistula has 39 phyto-chemicals (PC) with accepted structures in thePubChem database[R14]. Table-1 enumerates the details. These were verified and matched. [R-15, 16, 17 and 18]. Ro5 and Toxicity Studies Plants contain divergent compounds including toxins & toxicity up-regulators. Medicinal plants (as a rule) contain the least & normally the most unstable\auto degrading toxins, hence = medicinal. © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 149 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 Psoriasis also responds\becomes unstable transiently to sub-clinical doses of (nearly all) toxins. Finally rebounds. We are interested in a non-toxic route of therapeutics (pregnancy safe). Therefore, toxicity evaluation is priority. The 17 PCs which qualified the RO5 test were again studied via ProTox-II server to check their Toxicity (https://mcule.com/apps/toxicity-checker/)[R19](https://tox-new.charite.de/protoxII/). Hence, Lipinski's Rule of Five (RO5) study was carried out using TargetNet web server (standard tool for such purposes) and 17 out of the 39 (43.58%) phyto compounds (PC) satisfied all the rules (Table 2). Out of the 17 PCs, 16 (94.12%) are found to be Non-Toxic (Table 3). These 16 PCs were finally taken for the docking study against TRPV3 protein. RESULTS (TOXICITY) Table-1: Description of Phytochemical compounds present in Cassia fistula SL. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Chemical name Cyclopentasiloxane, Decamethyl Cyclohexasiloxane, dodecamethyl Citronellol Isophytol 1,3-Cyclopentadiene, 5(1-methylethylidene)Phytol Pyridine Linolenic acid Oxyanthraquinone dihydroxyanthraquinone Molecular formula C10H30O5Si5 PMID SMILE ID 10913 C[Si]1(O[Si](O[Si](O[Si](O[Si](O1)(C)C)(C)C)(C)C)(C)C)C C12H36O6Si6 10911 C[Si]1(O[Si](O[Si](O[Si](O[Si](O[Si](O1)(C)C)(C)C)(C)C)(C)C)(C)C)C C10H20O C20H40O C8H10 8842 10453 137467 CC(CCC=C(C)C)CCO CC(C)CCCC(C)CCCC(C)CCCC(C)(C=C)O CC(=C1C=CC=C1)C C20H40O C5H5N C18H30O2 C14H9NO3 C22H28N4O6 C15H14O5 C15H14O6 C30H26O12 5280435 1049 5280934 8323 4212 443639 72276 122738 C15H8O6 C21H18O11 10168 5320961 CC(C)CCCC(C)CCCC(C)CCCC(=CCO)C C1=CC=NC=C1 CCC=CCC=CCC=CCCCCCCCC(=O)O C1=CC=C2C(=C1)C(=O)C3=C(C=CC(=C3C2=O)O)N C1=CC(=C2C(=C1NCCNCCO)C(=O)C3=C(C=CC(=C3C2=O)O)O)NCCNCCO C1C(C(OC2=CC(=CC(=C21)O)O)C3=CC=C(C=C3)O)O C1C(C(OC2=CC(=CC(=C21)O)O)C3=CC(=C(C=C3)O)O)O C1C(C(OC2=C1C(=CC(=C2C3C(C(OC4=CC(=CC (=C34)O)O)C5=CC(=C(C=C5)O)O)O)O)O)C6=CC(=C(C=C6)O)O)O C1=CC2=C(C(=C1)O)C(=O)C3=C(C2=O)C=C(C=C3O)C(=O)O C1=CC2=C(C(=C1)OC3C(C(C(C(O3)CO)O)O)O)C(=O)C4=C(C2=O)C=C(C=C4O)C (=O)O C1=CC2=C(C(=C1)OC3C(C(C(C(O3)CO)O)O)O)C(=O)C4=C (C2C5C6=C(C(=CC=C6)OC7C(C(C(C(O7)CO)O)O)O)C(=O)C8=C5C=C(C=C8O)C( =O)O)C=C(C=C4O)C(=O)O C1=CC2=C(C(=C1)OC3C(C(C(C(O3)CO)O)O)O)C(=O)C4=C (C2C5C6=C(C(=CC=C6)OC7C(C(C(C(O7)CO)O)O)O)C(=O)C8=C5C=C(C=C8O)C( =O)O)C=C(C=C4O)C(=O)O CC1=CC2=C(C(=C1)O)C(=O)C3=C(C2=O)C=CC=C3O CC1=CC2=C(C(=C1)O)C(=O)C3=C(C2=O)C=C(C=C3O)OC C1=CC(=CC=C1C2=C(C(=O)C3=C(C=C(C=C3O2)O)O)O)O C1CC2=C(C(=C(C=C2O)O)C3CC(OC4=C3C(=CC(=C4C5CC(OC6=C(C (=CC(=C56)O)O)C7CC(OC8=CC(=CC(=C78)O)O)C9=CC=C(C=C9)O)C2=CC=C (C=C2)O)O)O)C2=CC=C(C=C2)O)OC1C1=CC=C(C=C1)O CC1=C(C(=C2C(=C1O)C(=O)C3=CC(=C(C=C3C2=O)OC)OC)O)C(=O)O C1C(C(OC2=CC(=CC(=C21)O)O)C3=CC(=C(C=C3)O)O) OC4(C(C(C5=C(C=C(C=C5O4)O)O)O)O)C6=CC(=C(C=C6)O)O C1C(C(OC2=CC(=CC(=C21)O)O)C3=CC(=C(C=C3)O)O)O CCOC(=O)C1=CC=CC=C1C(=O)OCC C(C#N)C(=O)NC(=O)N COC1=CC=CC(=C1OC)C(=O)N C1=CC=C(C=C1)C2=NC(=S)NN2C3=CC=CC=C3 14. 15. epiafzelechin epicatechin procyanidin B2 rhein rhein glucoside 16. sennoside A C42H38O20 73111 17. sennoside B C42H38O20 91440 18. 19. 20. 21. chrysophanol physcion Kaempferol leucopelargonidin tetramer C15H10O4 C16H12O5 C15H10O6 C60H50O16 10208 10639 5280863 102115508 22. 23. Fistulic acid Proanthocyanidins C18H14O8 C30H26O13 53438729 122173182 24. 25. 26. 27. 28. Catechin Diethyl Phthalate Cyanoacetylurea o-Veratramide 1,5-Diphenyl-2H-1, 2, 4-triazoline -3-thione Sarcosine Patuletin Methyl succinic acid Menisdaurin Robustaflavone C15H14O6 C12H14O4 C4H5N3O2 C9H11NO3 C14H11N3S 9064 6781 74055 220089 2802516 C3H7NO2 C16H12O8 C5H8O4 C14H19NO7 C30H18O10 1088 5281678 10349 6440400 5281694 C13H16O10 124021 C27H32O16 6443665 36. 37. 1-Galloyl-Beta-Dglucose Hydroxysafflor yellow A Undulatoside A Procyanidin B2 C16H18O9 C30H26O12 5321494 122738 38. Rindoside C35H42O21 46174003 39. Orlistat C29H53NO5 3034010 29. 30. 31. 32. 33. 34. 35. CNCC(=O)O COC1=C(C2=C(C=C1O)OC(=C(C2=O)O)C3=CC(=C(C=C3)O)O)O CC(CC(=O)O)C(=O)O C1C(C=CC(=CC#N)C1OC2C(C(C(C(O2)CO)O)O)O)O C1=CC(=CC=C1C2=CC(=O)C3=C(O2)C=C(C(=C3O)C4=C(C=CC(=C4)C5= CC(=O)C6=C(C=C(C=C6O5)O)O)O)O)O C1=C(C=C(C(=C1O)O)O)C(=O)OC2C(C(C(C(O2)CO)O)O)O C1=CC(=CC=C1C=CC(=C2C(=C(C(=O)C(C2=O) (C3C(C(C(C(O3)CO)O)O)O)O)C4C(C(C(C(O4)CO)O)O)O)O)O)O CC1=CC(=O)C2=C(C=C(C=C2O1)OC3C(C(C(C(O3)CO)O)O)O)O C1C(C(OC2=C1C(=CC(=C2C3C(C(OC4=CC(=CC(=C34) O)O)C5=CC(=C(C=C5)O)O)O)O)O)C6=CC(=C(C=C6)O)O)O CC(=O)OCC1C(C(C(C(O1)OC2C(C3(CCOC(=O)C3=CO2)O) C=C)OC(=O)C)OC(=O)C)OC(=O)C4=C(C(=CC=C4)OC5C(C(C(C(O5)CO)O)O)O)O CCCCCCCCCCCC(CC1C(C(=O)O1)CCCCCC)OC(=O)C(CC(C)C)NC=O © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 150 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 Table-2: Lipinski’s RO5 study was using TargetNet showed 17 out of the 39 PCs (43.58%) satisfied all the rules SL. NO PHYTOCHEMICALS NAME 1. Cyclopentasiloxane, Decamethyl Cyclohexasiloxane, dodecamethyl Citronellol Isophytol 1,3-Cyclopentadiene, 5-(1methylethylidene)Phytol Pyridine Linolenic acid Oxyanthraquinone dihydroxyanthraquinone epiafzelechin epicatechin Procyanidin B2 rhein rhein glucoside sennoside A sennoside B chrysophanol physcion Kaempferol Leucopelargonidin tetramer Fistulic acid Proanthocyanidins Catechin Diethyl Phthalate Cyanoacetylurea o-Veratramide 1,5-Diphenyl-2H-1, 2, 4triazoline -3-thione Sarcosine Patuletin Methyl succinic acid Menisdaurin Robustaflavone 1-Galloyl-Beta-D-glucose Hydroxysafflor yellow A Undulatoside A Procyanidin B2 Rindoside Orlistat 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. S.N. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. TPSA (Topological polar surface area) (<140) 46.15 MR (Molar Refractivity) (40-130) MOLECULAR WEIGHT (<=500 D) HBA1Hydrogen bond acceptors (<=10) 10.0 LogP (<=5) Lipinski rule of five 370.7697 HBDHydrogen bond donor (<=5) 0.0 92.835 3.592 75% 55.38 111.402 444.92364 0.0 12.0 4.3104 75% 20.23 20.23 0.0 50.8718 98.9798 37.034 156.2652 296.531 106.165 1.0 1.0 0.0 1.0 1.0 0.0 2.7513 6.3625 2.4488 100% 75% 100% 20.23 12.89 37.3 80.39 163.18 90.15 110.38 220.76 111.9 191.05 347.96 347.96 74.6 83.83 111.13 279.68 130.36 229.99 110.38 52.6 95.98 61.55 65.7 98.9418 24.237 88.9898 66.1764 119.1754 72.3108 74.3338 146.7126 70.7543 102.8765 202.796 202.796 68.761 75.253 76.012 278.731 88.7043 147.5216 74.3338 58.615 27.3891 47.5209 74.1847 296.531 79.0999 278.4296 239.22616 444.48092 274.26866 290.26806 578.52024 284.22042 446.36102 862.73912 862.73912 254.2375 284.26348 286.2363 1027.0294 358.29896 594.51964 290.26806 222.23716 127.1014 181.18854 253.32224 1.0 0.0 1.0 2.0 8.0 4.0 5.0 10.0 3.0 6.0 12.0 12.0 2.0 2.0 4.0 12.0 3.0 10.0 5.0 0.0 2.0 1.0 1.0 1.0 1.0 2.0 4.0 10.0 5.0 6.0 12.0 6.0 11.0 20.0 20.0 4.0 5.0 5.0 16.0 8.0 13.0 6.0 4.0 5.0 4.0 2.0 6.3641 1.0816 5.6605 2.331 0.7886 1.8405 1.5461 2.995 1.5714 -0.9555 -1.0956 -1.0956 2.1816 2.1902 2.2824 11.1872 1.897 2.7327 1.5461 2.04 0.18618 1.503 3.5969 75% 100% 75% 100% 50% 100% 75% 25% 100% 50% 25% 25% 100% 100% 100% 0.0% 100.% 25% 75% 100% 100% 100% 100% 49.33 140.59 74.6 143.4 181.8 177.14 34.14 149.82 220.76 299.03 81.7 21.1085 84.527 29.6926 71.964 146.972 71.4437 67.52 83.6182 146.7126 177.1415 145.3637 89.09318 332.26168 132.11462 313.30316 538.45792 332.26014 224.25458 354.30872 578.52024 798.69538 495.73482 2.0 5.0 2.0 5.0 6.0 7.0 0.0 5.0 10.0 6.0 1.0 3.0 7.0 4.0 8.0 8.0 10.0 2.0 8.0 12.0 21.0 6.0 -0.3187 1.9966 0.1818 -2.05772 5.134 -2.2399 2.7243 -1.0143 2.995 -2.0153 7.9087 100% 75% 100% 75% 25% 50% 100% 75% 25% 25% 75% Table-3: Toxicity checking the phtocompounds using protox-ii tool Phytocompound Tool Toxic/Non-Toxic Citronellol ProTox-II NON-TOXIC 1,3-Cyclopentadiene, 5-(1-methylethylidene)ProTox-II NON-TOXIC Pyridine ProTox-II NON-TOXIC Oxyanthraquinone ProTox-II NON-TOXIC epiafzelechin ProTox-II NON-TOXIC rhein ProTox-II NON-TOXIC chrysophanol ProTox-II NON-TOXIC physcion ProTox-II NON-TOXIC Kaempferol ProTox-II NON-TOXIC Fistulic acid ProTox-II NON-TOXIC Diethyl Phthalate ProTox-II NON-TOXIC Cyanoacetylurea ProTox-II NON-TOXIC o-Veratramide ProTox-II NON-TOXIC 1,5-Diphenyl-2H-1, 2, 4-triazoline -3-thione ProTox-II NON-TOXIC Sarcosine ProTox-II NON-TOXIC Methyl succinic acid ProTox-II NON-TOXIC Hydroxysafflor yellow A ProTox-II TOXIC © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 151 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 Prediction of Binding Site The binding site of TRPV3 was identified by Computed Atlas of Surface Topography of Proteins (CASTp) [R-20]. The consensus results depict the active site residues that take part in the binding site formation. Lipinski rule of five and Toxicity studies Lipinski rule of five – Ro5 The RO5[R-21] states that (in insilico studies) any oral active drug should satisfy the rules such as Molecular mass (<=500 D), log P (<=5), Hydrogen bond donor (<=5), Hydrogen bond acceptors(<=10), Molar refractivity(40-130). This is the primary selection criteria. Violation of any one of the rule disqualifies the candidate compound as a potential source. Target Net web server [R-22] has been used to predict the RO5 for all the 39 PC’s (http://targetnet.scbdd.com/calcnet/calc_rule_text/#). Molecular Docking of PCs & reported drugs against TRPV3 Auto Dock, is a well-known molecular docking tool that is widely used for the screening of compounds against potential targets. We have used Auto Dock 4.2 tool [R-23] for molecular docking studies using computationally predicted and validated structure of TRPV3 against the 16non toxic PCs. The best-docked complexes were characterized and processed for further computational analysis based on binding energy values, ligand efficiency, intermolecular hydrogen (H)-bonds, and other hydrophobic and electrostatic interactions. For topical levity 5 commercial allopathic drugs namely, Coaltar [R-25], Acitrtin [R-26], Calcipotriol [R-27], Tazarotene [R-28] and ‘Nelarabine’(liquid cancer drug repurposed as antipsoriasis) [R-29] have been presented. RESULTS The gene TRPV3 is the most common and predominant in psoriasis. It is also involved in hypersensation and in psoriatic pruritus. Hence, TRPV3 has been taken for the study. The crystal structure of Sl. No. 1. 2. 3. 4. 5. 6. TRPV3’s protein was collected from RCSB PDB pdb id 6dvz [R-29]. The chain A of the structure was selected for in silico investigation. From castp web server the binding site of the protein were obtained.The binding sites predicted of the protein are as follows : LYS 253, TYR524, THR937,ASP400,ASN401,GLU405, ILE406, VAL408, TYR 409,ASN410,THR 411,ASN412, ARG416, PHE 441, SER444, PHE447, TYR448, TYR451, TRP493,CYS496, ILE497, LYS500, GLU501, ILE503, ALA504, LEU507,LEU508, ARG509, PRO510,ASP512, LEU513, GLN514, SER515, ILE516, ASP519, ALA520, PHE 522, HIS523, PHE524, PHE526, PHE527,ALA564, TYR565, ARG567, LEU594, GLN695, ARG698, THR699, LEU701, GLU702, GLU704, LYS705 and MET706. The grid box value taken for the study is with X-dimension = 76, Y-dimension = 110 and Zdimension =98 with spacing 0.375 Angstrom. Molecular docking The binding free energies of TRPV3 with all the 16 screened PCs and 5 commercially available allopathic drugs namely, Coaltar, Acitrtin, Calcipotriol, Tazarotene and Nelarabine interaction complexes are presented in Table 4 and Table 5, respectively. Out of the 16 PCs from Cassia fistula 3 PCs showed higher binding affinity. Chrysophanol showedthe highest@ 7.58 kcal/mol, followed by Oxyanthraquinone with6.77 kcal/mol and Rhein -6.73 kcal/mol., respectively. Figure 2 shows the 2D and 3D structures of Chrysophanol. Figure 3 and 4 shows the 2D and 3D structure of Chrysophanolrespectively. Figure 5 and 6 shows the 2D and 3D interaction of TRPV3 protein and Oxyanthraquinone respectively. Figure 7 and 8 shows the 2D and 3D interaction of TRPV3 protein and Rhein Complex respectively. Among the 4 anti-psoriasis allopathic drugs, Tazarotene showsan high binding affinity of -7.82 kcal/mol. However, ithas only 1‘H’ atom = bonding uncertainty. Similarly, Nelarabine the re-purposed drug has an binding affinity of only -4.11 kcal/molwhich is less by an order ranging between 8095 % vis-à-vis Chrysophanol, Oxyanthraquinone& Rhein..And Calcipotriol is found to be toxic via ProTox-II server test (Table - 6). Table-4: Docking of screened Compounds from Cassia fistula against TRPV3 protein of Psoriasis Phytocompound Binding Ligand Inhibition No. of H-Bond Forming Average Energy(kcal/ Efficiency Constant H Residues Distance of Mol) (µm) Bonds H-Bonds (Å) Citronellol -3.63 -0.33 2.17 2 LYS705,GLU405 2.506685 1,3-Cyclopentadiene, 5- -4.18 -0.52 858.34 N/A N/A N/A (1-methylethylidene)Pyridine -3.43 -0.57 3.06 N/A N/A N/A Oxyanthraquinone -6.77 -0.38 10.84 3 HIS426,LEU420, 2.485776667 ARG693 epiafzelechin -6.04 -0.3 37.19 4 TYR409,LYS500 2.7273075 Rhein -6.73 -0.32 11.7 2 HIS426,ARG693 2.34932 © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 152 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 7. 8. 9. Chrysophanol physcion Kaempferol -7.58 -6.25 -6.4 -0.4 -0.3 -0.3 2.8 26.21 20.41 3 1 4 10. Fistulic acid -6.71 -0.26 11.98 4 11. 12. 13. 14. Diethyl Phthalate Cyanoacetylurea o-Veratramide 1,5-Diphenyl-2H-1, 2, 4-triazoline -3-thione Sarcosine Methyl succinic acid -5.0 -4.85 -3.88 -5.79 -0.31 -0.54 -0.3 -0.32 215.98 280.84 1.44 56.96 -3.55 -5.79 -0.59 -0.64 2.52 56.56 15. 16. Sl. No. 1. 2. 3. 4. 5. 2.378486667 2.54824 2.1602375 1 3 1 N/A HIS426,LEU420 HIS417 LYS705,GLU405, PRO510,ASN410 TRP433,PHE569, ARG696 HIS430 GLU704,THR397 ALA560 N/A 3 1 LYS705,GLU405 LYS435 2.263403333 2.77716 3.0264625 2.8415 2.076243333 2.00649 N/A Table-5: Docking of Allopathic Licenced Drug Moieties against TRPV3 protein of Psoriasis Phytocompound Binding Ligand Inhibition No. of H-Bond Forming Average Energy Efficiency Constant H Residues Distance of (kcal/Mol) (µm) Bonds H-Bonds (Å) Nelarabine -4.11 -0.2 972.2 3 ARG567,GLU501, 2.552373333 (FDA APPROVED PHE522 DRUG REPORTED) coal tar -6.57 -0.47 15.38 N/A N/A N/A acitretin -7.51 -0.31 3.13 1 ASP519 2.0084 Calcipotriol -7.68 -0.26 2.33 2 TYR565,ALA564 2.151095 Tazarotene -7.82 -0.31 1.86 1 ARG567 3.28192 S.N. 1. 2. 3. 4. 5. Table-6: TOXICITY off Table 5 members via ProTox-II tool Phytocompound Tool Toxic/Non-Toxic ProTox-II NON-TOXIC Nelarabine (FDA APPROVED DRUG REPORTED) coal tar ProTox-II NON-TOXIC acitretin ProTox-II NON-TOXIC Calcipotriol ProTox-II TOXIC Tazarotene ProTox-II NON-TOXIC Fig-2: Shows the 2D and 3D structure of Chrysophanol © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 153 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 Fig-3: Shows the 2D interaction of TRPV3 protein and Chrysophanol Complex Fig-4: Shows the 3D interaction of TRPV3 protein and Chrysophanol Complex Fig-5: Shows the 2D interaction of TRPV3 protein and Oxyanthraquinone Complex Fig-6: Shows the 3D interaction of TRPV3 protein and Oxyanthraquinone Complex © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 154 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 Fig-7: Shows the 2D interaction of TRPV3 protein and Rhein Complex Fig-8: Shows the 3D interaction of TRPV3 protein and Rhein Complex Table-7: Suggestive Multi-Disciplinary Versatile Therapeutic Method (Model). For* 1 [a] Nelarabine [a] 300 mg/ m² Chrysophanol [b] Rhein [c] Tazarotene [d] Admix [e] xx xx xxx ‘a’ is administered IV as in ‘a’ + an admixture of b+c+d orally as in ‘b’ 2[b] C. fistula [f ] xx Form # IV 100-300 mcg xxx xx FD-T\C ‘a & b’ only. Orally. -Do3[c] 100-300 mcg xx Admixed with 500mg Banana or sweet Dry powder; -Do4[c] 100-300 mcg corn porridge or bark\any -Do5[d] sugar cane jiggery as ‘a & c’ only. other along -DoRest : as in ‘a & d’ only. buffering food. with ‘a’ ‘b’ Rest : as in ‘c’ 6[e] xx Range: clinical assessment basis. For* = Formulation. Mg =milligram; mcg = micro gram; IV = intravenous. FD-T\C = fixed dose tablet\Capsule. More works on. As IV with Nor Sal @ 500ml. + others Currently used standalone repurposed therapy. Table – 7 gives a suggestive therapeutic method. It is complementing compound based holistic and functional food concept. Nelarabine ‘a’ = a chemotherapy medication used for the treatment of Tcell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma i.e., autosomal recessive diseases marked by Purine nucleoside phosphorylase deficiency which is addressed by IV infusion of Nelarabine. Repurposed usage; expensive; case specific complication\delayed side effects. Nevertheless, Soriasis returns (there is however no reports\instances of Rebound phenomena). Chrysophanol ‘b’ = used for cooling blood (circulation control to an inflamed brain, & bowl loop relaxing. Rhein ‘c’= (protector of systemic physiological processes) viz., is hepato-protective, nephro-protective, anti-cancer, anti-inflammatory, and several other protective effects; versatile. Tazarotene ‘d’= already being used to treat Psoriasis; dermis target molecule (vital for our objectives). Nelarabine (no indulgence) is only a representative candidate any of the known antisoriasis medication can benefit due to concurrent use of C.Fistula as functional food (home made-hand made) and extra mural nursing [29;30]. Using NanoTechnology such unique combination can be formulated as a mini pill Fixed Dose [31]. NOTE: Nelarabine is only a case study candidate to highlight the scenario of “mixo-pathy” i.e., complementing application of synergistic items with family welfare as the objective. No commerce. No indulgence. That, e.g., Formulation „f‟ a toxic moiety can be repurposed for use@ 1/3rd potency further tapered to a single infusion for 3 continuous months (30 days interval in-between each sub-clinical IV dosing) in hospital setting while C Fistula bark powder (made sterile by Gamma radiation @ 20 Kilo Gray) can be orally chewed taken/as a capsule @ 500mg daily for all the 90 days therapy period. Atomic Composition Comparison Fig-9 is the Graph of the atomic composition Chrysophanol: C15H10O4, Molar mass: 254.24 (Blue); Rhein: C15H10O5; 284.22042 (Maroon) and Oxyanthraquinone: C27H32O3 239.22616 (Green). Chrysophanol and Rhein (maroon) suggest inter- © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 155 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 synergy. Oxyanthraquinone(green) posits as member inhibitor. Fig-10 is the Graph of the atomic composition of Coaltar: assumed as 000 (Blue) {*}, Acitrtin: C21H26O3, (Meroon); Calcipotriol: C27H40O3, Tazarotene: C21H21NO2S (Green); and Nelarabine C11H15N5O5 (Violet). Tazarotene (green) posits as the broad spectrum efficacy inducer cum potency upregulating member. Chrysophanol and Rhein double up as process scavengers (*). CT has more than 1000 compounds ! hence we have assumed hypothetical values of C0H0O0 for its structure. Juxtaposing the results of Fig-9 & Fig 10 prima facie an clinical synergy is suggested between Nelarabine and PCs Chrysophanol and Rhein as functional food\adjuncts and Tazarotene potency upregulating cum in-blood life lengthening member (others, variedly). Fig-9: The Graph of the atomic composition Chrysophanol: C15H10O4, (Blue); Rhein : C15H10O5; 284.22042 (Maroon) and Oxyanthraquinone : C27H32O3&239.22616(Green). Chrysophanol and Rhein (maroon) suggest inter-synergy. Oxyanthraquinone (green) posits as member inhibitor Fig-10: The Graph of the atomic composition of Coal tar: assumed as 000 (Blue) {*}, Acitrtin: C21H26O3, (Meroon); Calcipotriol: C27H40O3, Tazarotene: C21H21NO2S (Green); and Nelarabine C11H15N5O5 (Violet). Tazarotene (green) posits as the broad spectrum efficacy inducer cum potency up-regulating member. Chrysophanol and Rhein doubling up as process scavengers (*). CT has more than 1000 compounds ! hence we have assumed hypothetical values of C0H0O0 for its structure DISCUSSION & THEORY Atoms are important in affecting bonding and the most vital being ‘H’ atom. Although Oxyanthraquinone have higher ‘H’ atoms, it is the presence of heavy atoms that down regulates its bonding affinity. The electro-negativity of the C atoms is as much as that of the H atoms. C withdraws the majority of the electrons from the electron dense covalent bond with the H’s leaving the H atom electrondeficient [33]. Thus the electron depleted H atom thence is as alike an bare proton (large mass vagabond member), susceptible to wandering & bond unpredictability [34;35] this is of special relevance in poly-morphysim in neoplasias. C is also a heavy member as compared to H. Additionally becauses degeneration of the H ion potential. If the C atoms in Oxyanthraquinone could be reduced to <16 then it will indicate nice affinity. The presence of S in Tazarotene enhances binding potential while N atom in Nelarabine thwarts bonding affinity and also exponentially raises © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 156 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 the disassociation constant.Removalof N atoms shall downturn the electro-negativity of this drug (making it more effective clinically in liquid cancers & psoriasis) and up-regulate Nelarabine’s efficacy to greater than Chrysophanol; and still more with addition of S. Nitrogen is the principal cause of Nelarabine’s large disassociation constant. Greater the disassociation less is the therapeutic consistency (inverse relationship). S has also been known for long as of having efficacy in dermal pathologies. This in-silico study vets it further. In anthropogenic physiological processes the lower be the binding energy the quicker be the docking and if the inhibition constant also be low then the intermolecular binding ‘likeness’ enlarges. Finally if the ‘H’ bond’s distance be less or of equal order (vis-à-vis known clinical compounds) it further matters much in process efficacy. This is because an H atom which is the driver ion cum bond signaling potential member has a variable diameter of < 75ppm (100ppm = 1 angstrom). Thus, Chrysophanol & Calcipotriol severally have more electron load in the inter-molecular bonds (space) resulting in better and failsafe docking and jointly shall indicate high clinical efficacy and strong anti-inhibition (viz., chronic status systemic pathogenic and systemic response mediated inhibitions). From such parameters, Chrysophanol; and Rhein (Table-4) score well among the PCs so also all the allopathic members as are in Table-5. CONCLUSION Chrysophanoland Rhein(Sl. No. 6,7 of T- 4) posit as the champion and runners-up respectively in this computational study. Chrysophanolshows the highest binding affinity against TRPV3. It is toxicologically safe. Indicates good efficacy at low potencies. Repurposed drug Nelarbine stands a good chance for re-engineering for better efficacy with greater safety indications (applicable also in its present naïve form). The trio can be expected as future antipsoriasis drug candidates; starting material; SOS application; etc. Existing anti-psoriasis conventional drugs are likely to yield results whence Chrysophanoland\or Rheinare co-administered as functional food or as therapeutic/s on fixed dose basis. Even MDT (multi-drug therapy) approach posits promising being comprised of any of the members of Table-5 + Nelabrine + Chrysophanoland\or Rhein as functional food or as adjunct herbal medicament. S stands validated in dermal pathologies. N not. Oxyanthraquinone is discounted as there is a barrier\inhibition between it & Chrysophanol (correlate with Fig-3). Table – 7 is helpful for the (i) Family Physician (ii) small manufacturers (iii) local sustainable employment creation (iv) reduce Carbon Foot Print. This study is noncommercial; is indicative; not exhaustive. ACKNOWLEDGEMENT We are thankful to the support staff in respective offices. They helped in various manners so that we could complete this very difficult paper. We are especially indebted to ordinary folks for they helped us with the valuable data that C Fistula is abundant all over the tropo-equatorial belts and specially is accessible for free by the citizens. DECLARATIONS OF INTEREST Authors declare that they have no conflict of interest. This study is noncommercial; not funded; non donor driven. REFERENCES 1. Richardson, S. K., & Gelfand, J. M. (2008). Update on the natural history and systemic treatment of psoriasis. Advances in dermatology, 24, and 171. 2. American academy of Dermatology. (https://www.aad.org/public/diseases/psoriasis/wha t/causes#:~:text=When%20a%20person%20has%2 0psoriasis, skin%2C%20and%20you%20see%20psoriasis.) 3. Pawar, A. V., & Killedar, S. G. (2017). Uses of Cassia fistula Linn as a medicinal plant. International Journal for Advance Research and Development, 2(3). 4. Szallasi, A. (Ed.). (2015). TRP channels as therapeutic targets: from basic science to clinical use. Academic Press. 5. Jothy, S. L., Zakaria, Z., Chen, Y., Lau, Y. L., Latha, L. Y., &Sasidharan, S. (2011). Acute oral toxicity of methanolic seed extract of Cassia fistula in mice. Molecules, 16(6), 5268-5282. 6. Charak Samhita c.4th A.D., of Agnivesa, Bramhanand Tripathy ed., 2 Vols. (1969). Chaukhamba Surabharati Prakashan, Varanasi, 1973. AND Charak Saamhita of Agnivesh, 2Vols., Ed. Kashinath Sastri and Gorakhnath Chaturvedi, Chowkhamba Vidyabhavan,Varanasi. 7. Bhattacharya, D. (2014). Select Palm Leaf Manuscripts Of Health Care Sciences, Indian Journal of History of Science, Indian National Science Academy, 49(3), 294-97. 8. Read, B. E., & LI, S. C. (1936). Chinese Medicinal Plants from the Pen Ts' ao Kang Mu [of Li Shihchên]... of a Botanical, Chemical and Pharmacological Reference List, Etc. Peking natural history bulletin. 9. Ayurvedic, P. (2016). AYUSH, govt of india, pharmacopoeia commission for indian medicine …, Extracts (monograph), Part-I, 9, 95-98. https://www.easyayurveda.com/2016/05/11/indiansenna-cassia-angustifolia/. 10. TheAyurvedic Formulary of India Part-I vol-VI, 2nd Edition. (2003). The Controller of publications, Govt. of India, Civillines, New Delhi. 11. Rastogi, R. P., & Mehrotra, B. N. (1999). Compendium of Indian Medicinal Plants Central © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 157 Chandra Sekhar Tripathy et al.; Saudi J Med, Mar, 2022; 7(3): 148-158 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. Drug Research institute Luck now and National institute of Science communication. New Delhi, 280. Hari, Om. S., & Brahmam, M. (1994). The Flora of Orissa, 4 vols. RRL, CSIR, Bhubaneswar, (2198 pages). Sharma, P. C., Yelne, M. B., Dennis, T. J., Joshi, A., &Billore, K. V. (2000). Database on medicinal plants used in Ayurveda. Kim, S., Thiessen, P. A., Bolton, E. E., Chen, J., Fu, G., Gindulyte, A., & Bryant, S. H. (2016). PubChem substance and compound databases. Nucleic acids research, 44(D1), D1202-D1213. Kulkarni, A., Govindappa, M., Ramachandra, Y. L., & Koka, P. (2015). GC-MS analysis of methanol extract of Cassia fistula and its in vitro anticancer activity on human prostate cancer cell line. Indo Am J Pharm Res, 5(2), 937-44. Bahorun, T., Neergheen, V. S., &Aruoma, O. I. (2005). Phytochemical constituents of Cassia fistula. African journal of Biotechnology, 4(13). Bhagyashree, B., Namdev, G., Supriya, M., Ramesh, K., Suhas, P., & Sankunny. M. K. (2018). Efficacy of Methanol Extract of Cassia Fistula Linn Stem Bark against Different Virulence Factors of the Human Pathogen Candida albicans. Aabideen, Z. U., Mumtaz, M. W., Akhtar, M. T., Raza, M. A., Mukhtar, H., Irfan, A., & Saari, N. (2021). Cassia fistula Leaves; UHPLC-QTOFMS/MS based metabolite profiling and molecular docking insights to explore bioactives role towards inhibition of pancreatic lipase. Plants, 10(7), 1334. Kiss, R., Sandor, M., &Szalai, F. A. (2012). http://Mcule. Com: a public web service for drug discovery. Journal of cheminformatics, 4(1), 1-1. Binkowski, T. A., Naghibzadeh, S., & Liang, J. (2003). CASTp: computed atlas of surface topography of proteins. Nucleic acids research, 31(13), 3352-3355. Lipinski, C. A. (2004). Lead-and drug-like compounds: the rule-of-five revolution. Drug discovery today: Technologies, 1(4), 337-341. Yao, Z. J., Dong, J., Che, Y. J., Zhu, M. F., Wen, M., Wang, N. N., & Cao, D. S. (2016). Target Net: a web service for predicting potential drug–target interaction profiling via multi-target SAR models. Journal of computer-aided molecular design, 30(5), 413-424. Lokesh, R., & Kannabiran, K. (2016). A handbook on protein ligand docking tool: autodock4. Ibezim, A., Onah, E., Dim, E. N., & Ntie-Kang, F. (2021). A computational multi-targeting approach for drug repositioning for psoriasis treatment. BMC 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. Complementary Medicine and Therapies, 21(1), 18. Bhatia, A., Singh, B., Amarji, B., Negi, P., Shukla, A., &Katare, O. P. (2011). Novel stain‐free lecithinized coal tar formulation for psoriasis. International journal of dermatology, 50(10), 1246-1248. Carretero, G., Ribera, M., Belinchón, I., Carrascosa, J. M., Puig, L., Ferrandiz, C., & Psoriasis Group of the AEDV. (2013). Guidelines for the use of acitretin in psoriasis. Actas DermoSifiliográficas (English Edition), 104(7), 598-616. Scott, L. J., Dunn, C. J., & Goa, K. L. (2001). Calcipotriol ointment. American journal of clinical dermatology, 2(2), 95-120. Duvic, M. (1997). Tazarotene: a review of its pharmacological profile and potential for clinical use in psoriasis. Expert opinion on investigational drugs, 6(10), 1537-1551. Ibezim, A., Onah, E., Dim, E. N., &Ntie-Kang, F. (2021). A computational multi-targeting approach for drug repositioning for psoriasis treatment. BMC Complementary Medicine and Therapies, 21(1), 18. Agrawal, A., & Kulkarni, G. T. (2020). Molecular docking study to elucidate the anti-pruritic mechanism of selected natural ligands by desensitizing TRPV3 ion channel in Psoriasis: An in silico approach. Indian Journal of Biochemistry and Biophysics (IJBB), 57(5), 578-583. Bhattacharya, D. (2017). Nursing Defeats Cancer, Jor of Nursing & Health Care, 5(3), (juniper); https://juniperpublishers.com/jojnhc/archive.php Bhattacharya, D. (2021). Covid Nursing: Less Known Aspects. Saudi J Nurs Health Care. 4(10); 317-332. https://saudijournals.com/media/articles/SJNHC_4 10_317-332_810dT0H.pdf Bhattacharya, D. (2017). Nano Tech Tablet: A Concept, Novel Approaches In Drug Designing & Approaches, 2(2). Mavroyannis, C., & C. A. Winicler. (1962). The Reaction of Nitrogen Atoms with Hydrogen Atoms, Upper Atmosphere Chemistry Research Group, the Canadian Journal of Chemistry, 40, 240-45. McGill University, Montreal, Quebec. https://cdnsciencepub.com/doi/pdf/10.1139/v62041. https://courses.lumenlearning.com/cheminter/chapt er/hydrogenbonding/#:~:text=Hydrogen%20bonding%20occur s%20only%20in,H%20atom%20very%20electron %2Ddeficient © 2022 |Published by Scholars Middle East Publishers, Dubai, United Arab Emirates 158