Rational Drug Design (RANCANGAN OBAT RASIONAL) PDF [PDF]

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RATIONAL DRUG DESIGN (RANCANGAN OBAT RASIONAL)



Penemuan Obat Penemuan obat adalah sebuah usaha yang diarahkan pada suatu target biologis, yang telah diketahui berperan penting dalam perkembangan penyakit atau dimulai dari suatu molekul dengan aktivitas biologi yang menarik.



Hit and Lead 







A "hit" is a chemical compound that produces a result in a preliminary biochemical test indicating that the compound merits further study as part of a drug discovery project. A "lead" is a compound that has been selected from a group of hit compounds based on qualities such as the intensity of the biochemical effect that occurs when the compound is present (efficacy), or the absence of coincidental effects (specificity).



Penemuan Obat •



Lead discovery : Identifikasi suatu senyawa yang mempunyai aktivitas biologis spesifik.



•



Lead optimization : Aktivitas dan sifat suatu senyawa diuji, kemudian molekul baru dirancang dan disintesis untuk mendapatkan aktivitas atau sifat yang diinginkan



Penemuan Obat Pendekatan untuk lead discovery (penemuan senyawa pemandu)  Serendipity (luck)  Screening  Chemical Modification  Rational: 1. Struktur 3Dimensi target biologis (receptor-based drug design) 2. Struktur molekul kecil yang sudah terbukti aktif (pharmacophore-based drug design)



Penemuan Obat 1. Serendipity / ketidaksengajaan 1928 Fleming mempelajari Staphylococcus, tapi terjadi kontaminasi di plate oleh jamur. Diamati bahwa di area yang terkontaminasi jamur mengalami lisis. Jamur memproduksi senyawa yang menghambat pertumbuhan bakteri : penicillin



Penemuan Obat 2. Screening Pengujian acak aktivitas biologi sejumlah besar senyawa menghasilkan lead. Saat ini sudah berkembang inovasi untuk sintesis banyak senyawa sekaligus (combinatorial synthesis) dan pengujian terhadap banyak target (high-throughput screening). Contoh: Prontosil berasal dari zat warna yang menunjukkan aktivitas antibakteri.



Penemuan Obat 3. Chemical Modification Metode tradisional. Suatu senyawa analog dari senyawa aktif yang sudah diketahui, disintesis dengan modifikasi minor, menghasilkan peningkatan aktivitas biologi.



Keuntungan dan keterbatasan : Mendapatkan senyawa yang sangat mirip dengan senyawa asal.



Penemuan Obat 4. Rational Drug Design; Ex. - Cimetidine (Tagamet) Dimulai dari target biologis yang sudah valid, dan berakhir dengan obat yang secara optimal berinteraksi dengan target dan memicu aktivitas biologis yang diinginkan. Masalah: histamin memicu sekresi asam lambung. Diinginkan suatu antagonis histamin untuk mencegah sekresi asam lambung.



Analog Histamin disintesis dengan variasi struktur (modifikasi kimiawi) dan diuji. N-guanyl-histamine menunjukkan aktivitas antagonis = LEAD compound.



Penemuan Obat 4. Rational Drug Design Dimulai dengan merancang senyawa yang memenuhi persyaratan spesifik. Senyawa kemudian disintesis dan diuji. Selanjutnya molekul dirancang kembali, disintesis & diuji .....



Dari mana persyaratan spesifik diperoleh? Dua sumber: 1. Struktur 3Dimensi target biologis (receptor-based drug design) 2. Struktur molekul kecil yang sudah terbukti aktif (pharmacophorebased drug design)



Penemuan Obat Rational Drug Design - Pharmacophore-based Drug Design • Pengujian sifat/fitur molekul2 (ligan) kecil inaktif dan fitur molekul2 kecil yang aktif. • Menyusun hipotesis tentang gugus fungsi apa pada ligan yang dibutuhkan untuk aktivitas biologis, dan gugus fungsi apa yang menekan aktivitas biologis. • Menyusun ligan baru dengan gugus fungsi/kimiawi yang diperlukan dengan profil 3D/lokasi yang sama dengan ligan aktif. (“Mimic” the active groups)



Keuntungan: Tidak perlu mengetahui struktur target biologis



Penemuan Obat Rational Drug Design – Typical Pharmacophore-based Project • Struktur satu seri senyawa dengan aktivitas biologi tertentu sudah diketahui. Kemudian dirancang struktur senyawa baru dengan aktivitas biologis yang lebih tinggi.



• Struktur umum dan khas dari semua senyawa aktif dikumpulkan sebagai gugus “pharmacophophore.” • Sebuah molekul dirancang untuk menyerupai / mimic pharmacophore.



Penemuan Obat Rational Drug Design - Receptor-based Drug Design • Diuji struktur 3D dari target biologis (biasanya berupa struktur kristal sinarray); kalau bisa target yang sudah membentuk kompleks dengan molekul kecil (ligan) aktif. • Dicari gugus kimia spesifik yang berperan dalam interaksi antara protein target dan obat. • Merancang kandidat obat baru yang mempunyai pola interaksi yang sama terhadap target biologis. Keuntungan: Visualisasi memungkinkan rancangan langsung molekul



Penemuan Obat Rational Drug Design – Typical Receptor-based Project • Struktur protein yang berhubungan dengan kanker dalam kompleks dengan ligan inhibitor non selektif telah diketahui. Ini merupakan langkah awal untuk merancang inhibitor yang lebih selektif.



• Suatu molekul dapat dirancang mempunyai interaksi yang lebih optimal terhadap protein target dibanding inhibitor asli.



Penemuan Obat Rational Drug Design Typical projects tidak hanya receptor-based saja atau pharmacophore-based saja; tapi menggunakan kombinasi informasi dari keduanya, yang diharapkan sinergis.



LEAD STRUCTURE OPTIMIZATION (MODIFICATION)



DRUG DESIGN AND DEVELOPMENT



Stages 1. Identify target disease 2. Identify drug target 3. Establish testing procedures 4. Find a lead compound 5. Structure Activity Relationships (SAR) 6. Identify a pharmacophore 7. Drug design- optimising target interactions 8. Drug design - optimising pharmacokinetic properties 9. Toxicological and safety tests 10. Chemical development and production 11. Patenting and regulatory affairs 12. Clinical trials



DRUG DESIGN AND DEVELOPMENT 1. TARGET DISEASE Priority for the Pharmaceutical Industry • Can the profits from marketing a new drug outweigh the cost of developing and testing that drug? Questions to be addressed • Is the disease widespread? (e.g. cardiovascular disease, ulcers, malaria)



•



Does the disease affect the first world? (e.g. cardiovascular disease, ulcers)



• •



Are there drugs already on the market? If so, what are there advantages and disadvantages? (e.g. side effects)



•



Can one identify a market advantage for a new therapy?



DRUG DESIGN AND DEVELOPMENT 2. DRUG TARGETS A) LIPIDS



Cell Membrane Lipids



B) PROTEINS



Enzymes Carrier Proteins Structural Proteins (tubulin)



C) NUCLEIC ACIDS



DNA RNA



D) CARBOHYDRATES



Cell surface carbohydrates Antigens and recognition molecules



DRUG DESIGN AND DEVELOPMENT 2. DRUG TARGETS TARGET SELECTIVITY AND SPECIFICITY



Between species • • •



(Antibacterial and antiviral agents) Identify targets which are unique to the invading pathogen Identify targets which are shared but which are significantly different in structure



Within the body • • • •



Selectivity between different enzymes, receptors etc. Selectivity between receptor types and subtypes Selectivity between isozymes Organ selectivity



DRUG DESIGN AND DEVELOPMENT



3. TESTING DRUGS • Tests are required in order to find lead compounds and for drug optimization • Tests can be in vivo or in vitro • A combination of tests is often used in research programmes (have activity at other undesired targets)



DRUG DESIGN AND DEVELOPMENT 3. TESTING DRUGS – IN VIVO • Carried out on live animals or humans • Measure an observed physiological effect • Measure a drug’s ability to interact with its target and its ability to reach that target • Can identify possible side effects • Rationalisation may be difficult due to the number of factors involved • Drug potency - concentration of drug required to produce 50% of the maximum possible effect • Therapeutic ratio/index - compares the dose level of a drug required to produce a desired effect in 50% of the test sample (ED50) versus the dose level that is lethal to 50% of the sample (LD50)



DRUG DESIGN AND DEVELOPMENT 3. TESTING DRUGS – IN VIVO • Afinity of a drug for a receptor : measure of how strongly that drug binds to the receptor. • Effiacy : measure of the maximum biological effect that a drug can produce as a result of receptor binding. • The potency of a drug : the amount of drug required to achieve a defined biological effect



DRUG DESIGN AND DEVELOPMENT 3. TESTING DRUGS – IN VITRO • Tests not carried out on animals/humans Target molecules (e.g. isolated enzymes or receptors) Cells (e.g. cloned cells) Tissues (e.g. muscle tissue) Organs Micro-organisms (for antibacterial agents)



• More suitable for routine testing • Used in high throughput screening • Measure the interaction of a drug with the target but not the ability of the drug to reach the target • Results are easier to rationalise - less factors involved • Does not demonstrate a physiological or clinical effect • Does not identify possible side effects • Does not identify effective prodrugs



DRUG DESIGN AND DEVELOPMENT



4. THE LEAD COMPOUND



Introduction • A compound demonstrating a property likely to be therapeutically useful • The level of activity and target selectivity are not crucial • Used as the starting point for drug design and development • Found by design (molecular modelling or NMR) or by screening compounds (natural or synthetic) • Active Principle - a compound that is isolated from a natural extract and which is principally responsible for the extract’s pharmacological activity. Often used as a lead compound.



DRUG DESIGN AND DEVELOPMENT Sources of Lead Compounds



A) The Natural World



B) The Synthetic World



C) The Virtual World



Plantlife (flowers, trees, bushes) Micro-organisms (bacteria, fungi) Animal life (frogs, snakes, scorpions) Biochemicals (Neurotransmitters, hormones) Marine chemistry (corals, bacteria, fish etc)



Chemical synthesis (traditional) Combinatorial synthesis



Computer aided drug design



DRUG DESIGN AND DEVELOPMENT



 Lead discovery : Identifikasi suatu senyawa yang mempunyai aktivitas biologis spesifik.  Lead optimization : Aktivitas dan sifat suatu senyawa diuji, kemudian molekul baru dirancang dan disintesis untuk mendapatkan aktivitas atau sifat yang diinginkan.



Target Identification



Target Validation



Target Isolation, Gentechnique Production



Etablishment of a Molecule Test System Screening



3D Str. of Target Virtual Screening



De Novo Design



Lead Structure



Optimization



No 3D Str. of Target



Candidate



Pharmacophore



Objectives Once a lead compound has been identified:



 Must be systematically altered to obtain the desired properties (maximize the therapeutic index and minimize side effects)  Alternatively, a known agonist or substrate can be structurally modified to make an antagonist or an inhibitor (maintaining the structural characteristics associated with binding and specificity but not "activation" of the biological activity)



From the Lead Structure to Active Compound CH3 O



Therapeutic Target Lead Discovery



N H



Lead Optimization drug design Clinical Candidate Commerical Drug



CH3 O O



Br N



O H3C



N N H



H



H



H



Lipinski‘s rule of five In order to achieve efficient oral absorption and cell



permeability, drug candidates should have:  Less than five hydrogen bond donors (sum of OH and NH groups)  A molecular weight less than 500 Da  A log P less than 5



 Less than 10 hydrogen bond acceptors (sum of O and N atoms in the structure)



Which physicochemical Properties should An Active Compounds has?



Solubility and Absorption: slightly soluble, slightly absorbed C. Lipinski‘s rule of five: Mol. mass < 500 logP < 5 Hyd. Bond donors (N-H, O-H) < 5 Hyd. Bond acceptors (N, O) < 10 Less than 8 rotateable bonds Polar surface < 140 Å2



Influence the transport across membrane



From the Lead Structure to Active Compound



In the optimization process of a lead structure to a clinical active compound, the molecules will be bigger and more lipophil The following properties of a lead structure are desirable: Mol. Mass < 250 Low Lipophyli (logP