Drug Discovery & Development

Drug Discovery & Development

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  Drug discovery anddevelopment
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  Introduction • Development ofnew drug is a complex, time-consuming, and expensive process. • The new drug discovery involves the identification of new chemical entities (NCEs). • These NCEs can be sourced either through chemical synthesis or through isolation from natural products. • Initial success stories in new drug discovery came from medicinal chemistry inventions, which led to the need of development of higher number of chemical libraries through combinatorial chemistry. • This approach, however, was proven to be less effective in terms of overall success rate. • The second source of NCEs for potential use as drug molecules has been the natural products. Cinchona officinalis Quinine Artemisia annua Artemisinin
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  Classification of naturalsource of NCEs drug discovery processes • Bioactive compounds for direct use as drug, e.g. digoxin. • Bioactive compounds with structures which themselves may act as lead compounds for more potent compounds, e.g. paclitaxel from Taxus species. • The novel chemophore which may be converted into druggable compounds with/without chemical analoging. • Pure phytochemicals for use as marker compounds for standardization of crude plant material or extract. • Pure phytochemicals which can be used as pharmacological tools. • Herbal extracts as botanical drugs, e.g. green tea extract.
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  Advantages of drugdiscovery from natural resources • The selection of a candidate species for investigations can be done on the basis of long-term use by humans. After a certain point afterward, one may attempt upon synthesis of active molecule and reduce pressure on the resource. (eg. Rauwolfia serpentine, Digitalis purpurea). • Sometimes, drug discovery approaches lead to development of novel molecules derived from the source due to inherent limitations of the original molecule. • Natural resources as starting point has a bilateral promise of delivering the original isolate as a candidate or a semi-synthetic molecule development to overcome any inherent limitations of original molecule. Podophyllum hexandrum Podophyllin (having dose-limiting toxicities) etoposide Teniposide
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  Disadvantages of drugdiscovery from natural resources • Drug discovery and eventual commercialization would pressurize the resource substantially and might lead to undesirable environmental concerns. • Over a period of time, the intellectual property rights protection related to the natural products is going down and countries agreeing to Convention on Biological Diversity (CBD). The process of accessing the basic lead resource, benefit sharing during the commercial phase, etc. tend to impede the pace of discovery process at various phases irrespective of the concerns leading to such processes.
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  Druggability of IsolatedPhytochemical Compounds • Challenges in the new drug development are mainly encountered from two categories: a) the prevailing paradigm for drug discovery in large pharmaceutical industries b) technical limitations in identifying new compounds with desirable activity. • Koehn and Carter have enumerated the following unique features of the compounds isolated from natural products: Greater number of chiral centers Increased steric complexity Higher number of oxygen atoms Lower ratio of aromatic ring atoms to total heavy atoms Higher number of solvated hydrogen bond donors and acceptors Grater molecular rigidity Broader distribution of molecular properties such as molecular mass, octanol water partition coefficient, and diversity of ring systems
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  Selection of CandidatePlant Species for Screening Screening Approaches Random approach Ethnopharmacology approach Traditional system of medicine approach Zoo-pharmacognosy approach Screening for selected class of compounds like alkaloids, flavonoids, Screening of randomly selected plants for selected bioassays • The approach of ethnopharmacology essentially depends on empirical experiences related to the use of botanical drugs for the discovery of biologically active NCEs. • This process involves the observation, description, and experimental investigation of indigenous drugs • Andrographis paniculata was used for dysentery in ethnomedicine and the compounds responsible for the activity were isolated as andrographolide. • The traditional codified systems built up the empirical practices on strong conceptual foundations of human physiology as well as of pharmacology • The pharmaceutical processes have been more advanced as against the use of crudely extracted juices and decoctions in ethnomedicinal practices • They are well documented and widely institutionalized. Observation of the behavior of the animals with a view to identify the candidate plants for new drug discovery
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  Salix alba SalicinAspirin
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  Cinchona officinalis Quinine Primaquine Chloroquine
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  Artemisia annua Artemisinin Artesunate Artemether
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  Camptotheca officinata Camptothecan Rubetican Exatecan
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  Stages of ClinicalTrial
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  Clinical Protocol forlead molecules