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Noi Abordări Terapeutice Ale Compușilor Naturali Prin Tehnici De Farmacologie Computațională

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Noi Abordări Terapeutice Ale Compușilor Naturali Prin Tehnici De Farmacologie Computațională UNIVERSITATEA DIN BUCUREȘTI FACULTATEA DE BIOLOGIE TEZĂ DE DOCTORAT NOI ABORDĂRI TERAPEUTICE ALE COMPUȘILOR NATURALI PRIN TEHNICI DE FARMACOLOGIE COMPUTAȚIONALĂ Conducător științific: Prof. Dr. Speranța Avram Doctorand: Ana-Maria Udrea -București, 2018- Cuprins PARTEA I............................................................................................................... 6 1. INTRODUCERE ...................................................................................................... 6 2. STADIUL ACTUAL AL CUNOAȘTERII ....................................................................... 20 2.1. PATOLOGIILE PSIHIATRICE ................................................................................. 20 2.1.1. Receptori implicați în patologiile psihiatrice ................................................ 23 2.1.1.1. TRANSPORTORUL DE SEROTONINĂ- IMPLICAȚII ÎN PATOLOGIILE PSIHIATRICE ....................................................................................................... 23 2.1.1.2. RECEPTORUL SE SEROTONINĂ SUBTIPUL 1A- IMPLICARE ÎN PATOLOGII PSIHIATRICE................................................................................... 26 2.1.1.3. RECEPTORUL Α1 ADRENERGIC-IMPLICAREA ÎN PATOLOGIILE PSIHIATRICE ....................................................................................................... 27 2.1.2. Depresia ..................................................................................................... 29 2.1.2.1. DEPRESIA DATE GENERALE ............................................................... 29 2.1.2.2. MEDICAȚIA UTILIZATĂ ÎN TRATAREA DEPRESIEI ............................. 31 2.1.2.2.1. SSRI-urile ............................................................................................ 32 2.1.2.2.2. SNRI ..................................................................................................... 37 2.1.2.2.3. TCA și TeCA ........................................................................................ 38 2.1.2.2.4. MAOI și RIMA ...................................................................................... 40 2.1.2.3. DEPRESIA ȘI SARCINA ......................................................................... 41 2.1.2.4. NOI PERSPECTIVE ÎN TRATAREA DEPRESIEI ................................... 43 2.1.3. Schizofrenia ................................................................................................ 46 2.1.3.1. SCHIZOFRENIE DATE GENERALE ....................................................... 46 2.1.3.2. MEDICAȚIA UTILIZATĂ ÎN MANAGEMENT-UL SCHIZOFRENIEI........ 47 2.1.3.2.1. Antipsihoticele tipice ......................................................................... 48 2.1.3.2.2. Antipsihoticele atipice ....................................................................... 50 2.1.3.3. SCHIZOFRENIA ÎN SARCINĂ ................................................................ 53 2.1.4. Sindrom bipolar .......................................................................................... 54 2.1.4.1. Sindromul bipolar date generale .......................................................... 54 2.1.4.2. MEDICAȚIA UTILIZATĂ ÎN TRATAREA SINDROMULUI BIPOLAR ....... 56 2.1.4.2.1. Tratamentul simptomatologiei maniacale ........................................ 56 2.1.4.2.2. Tratamentul simptomatologiei depresive ......................................... 56 2 2.1.4.3. NOI PERSPECTIVE ÎN TRATAREA SINDROMULUI BIPOLAR ............. 59 2.2. AGENȚI PATOGENI-PATOLOGII MICROBIENE ......................................................... 59 2.2.1. Infecțiile bacteriene ................................................................................... 60 2.2.2. Infecțiile fungice .......................................................................................... 63 3. SCOPUL ȘI OBIECTIVELE LUCRĂRII ....................................................................... 69 PARTEA A II-A .................................................................................................... 72 1. MATERIALE ȘI METODE ........................................................................................ 72 1.1. MATERIALE ...................................................................................................... 72 1.2. METODE .......................................................................................................... 73 1.2.1. Drug-like ..................................................................................................... 73 1.2.1.1. REGULA DE 5 A LUI LIPINSKI ............................................................... 73 1.2.1.2.FILTRUL LUI GHOSE .............................................................................. 73 1.2.1.3. REGULA LUI VEBER .............................................................................. 74 1.2.1.4. REGULA LUI MUEGGE .......................................................................... 74 1.2.2. Materiale și metode strategie computațională compus din nucă, în tratamentul patologiilor microbiene. ...................................................................... 76 1.2.3. Studii QSAR ............................................................................................... 78 1.2.3.1. MODELUL QSARSERT .......................................................................... 80 1.2.3.2. MODELUL QSARΑ1 ............................................................................... 82 1.2.3.3. MODELUL QSAR5-HT1A ........................................................................ 84 1.2.3.4. MODELUL QSARTI ................................................................................. 86 1.2.4. Docare moleculară ..................................................................................... 90 1.2.5. In silico ADMET .......................................................................................... 91 1.2.6. Strategie computațională: Noi Derivați de tiouree, cu posibil efect antimicrobian- drug-like și predicție ADMET....................................................... 100 2. REZULTATE ȘI DISCUȚII ..................................................................................... 102 2.1 REZULTATE ȘI DISCUȚII DRUG-LIKE .................................................................... 103 2.1.1. Melatonină profil drug-like ........................................................................ 103 2.1.2.Resveratrol profil drug-like ......................................................................... 103 2.1.3. 1,8 cineol profil drug-like ........................................................................... 104 2.1.4. α-terpinol profil drug-like ........................................................................... 104 2.1.5. Acid clorogenic profil drug-like .................................................................. 105 3 2.1.6. Acid elagic profil drug-like ......................................................................... 106 2.1.7. Acid ursolic profil drug-like ........................................................................ 106 2.1.8. Colină profil drug-like ................................................................................ 107 2.1.9. Cumarină profil drug-like .......................................................................... 108 2.1.10. Germacrene D profil drug-like ................................................................ 108 2.1.11. Lavandulil acetat profil drug-like ............................................................. 109 2.1.12. Linalool profil drug-like ............................................................................ 110 2.1.13. Acetat de linalil profil drug-like ................................................................ 110 2.1.14. Luteolin profil drug-like ........................................................................... 111 2.1.15. Perlolirine profil drug-like ........................................................................ 111 2.1.16. Quercitin profil drug-like ......................................................................... 112 2.1.17. Trigonelline profil drug-like ..................................................................... 112 2.2. REZULTATE ȘI DISCUȚII QSAR ........................................................................ 114 2.2.1. Rezultate și discuții modelul QSARSERT ................................................. 114 2.2.2. Rezultate și discuții modelul QSARα1 ...................................................... 120 2.2.3. Rezultate și discuții modelul QSAR5-HT1A .............................................. 126 2.2.4. Rezultate și discuții modelul QSARTI ....................................................... 132 2.3. REZULTATE ȘI DISCUȚII DOCARE MOLECULARĂ .................................................. 142 2.3.1. Rezultatele docării moleculare pentru compusul natural resveratrol ........ 142 2.3.2. Rezultatele docării moleculare pentru compusul natural perlolirine .......... 146 2.3.3. Rezultatele docării moleculare pentru compusul natural melatonină ........ 151 2.3.4. Rezultatele docării moleculare pentru compusul natural luteolin .............. 156 2.3.5. Rezultatele docării moleculare pentru compusul natural quercitină .......... 161 2.3.6. Rezultatele docării moleculare pentru compusul natural germacrene D .. 166 2.3.7. Rezultatele docării moleculare pentru compusul natural lavandulil acetat 172 2.3.8. Rezultate docării moleculare pentru compusul natural acetat de linalil .... 178 2.3.9. Rezultatele docarii moleculare pentru compusul
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