Overview To Drug Design And Development Biology Essay

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There is probably no global enterprise changing as rapidly and as radically as human health. There is immense global pressure to develop drugs against deadly disease like cancer, AIDS, alzimers, anti-virals. Moreover, there is demand to develop species and ethinic group specific drugs. It is also needed to replace active molecules with new drugs because prolonged use of a drug develops resistance. However introducing a new drug in market is a prolonged process and needs lot of time and investment. Drug development costs have recently been calculated at US$ 4 to 8 hundred million per launch [1]. This inherently high cost takes into account and resources wasted because only one in five lead compounds makes to clinical use. An improvement to one in three might save over US$200 million per compound; a large proportion of failure is due to lack of developability [2].

Despite these needs and failures lot of advancement has been made in the field of durg discovery. Knowledge based resources i.e. completion of human genome project and its post annotation has given large number of molecular targets. The advent of human genome's publication now offered a great opportunity for the understanding of genetic makeup of diseases and furnishing new gene products and/or pathways as new targets that were previously were not known. Molecular genetics cell biology, molecular biology and genetic engineering as well as advancement in X-ray crystallography and solution state NMR have given new insight to explore 3D structure of macromolecules.

The theme of drug discovery is promising; compounds are selected from a much higher set (drug databank, Virtual library etc) by virtue of activity against specific target. These hits are reduced further by tests that confirm activity and access drug like properties (i.e. solubility metabolic stability); high throughput screening (HTS) is the most cost effective method of experimentation and the only practical way to screen a large library of compounds. This is present scenario to search new promising molecules i.e. lead compounds. For the present work we have selected "curcumin" as the lead compound. This molecules prolific therapeutic activity is well known. However it suffers from lack of optimal pharmacokinetic profile by virtue of which it is not considered as a drug so far. Taking poor pharmacokinetic profile into account we have designed curcumin conjugates. In drug discovery of new lead molecule more rational approaches were developed based around structure of ligand and receptors. This was set against a background of studying biological and physiological systems in animal tissues. Thus knowledge around molecular determinants that contribute to affinity and efficacy enabled a generation of specific and potent ligand molecules to be developed. For this, invitro screening in cell cultures became central theme for giving valuable information on SAR and pharmacophore construction. In this way, in theory, if the lead molecule fails there is sufficient information for causes of failures. This process is fantastically justified in development of several molecules [3].

The use of cell culture or animals as a model to develop selective drugs has its own pitfalls. Activity in animal or animal cell culture does not always translate into efficacy in humans. Since human is having well evolved system, pathways and receptors which makes significant differences in human and animal pathaolgy which can lead to no effects at safe doses in clinical trial. Now it is possible to work with specific target i.e. human receptor, enzymes and pathways due to advancement in cell biology and molecular biology to establish structure activity relationship. Chemists then expand promising lead compounds into libraries of analogues that undergo further round of testing. The iterative process of modeling, resynthesis and retesting leads to a few optimized candidates that go on to further evaluation, finally in clinical trials.

Prentis et al (1998); [4] suggested that phase I clinical trial failures before pre-clinical ADME(absorption, distribution, metabolism, excretion) is due to Pharmacokinetics 40%, Toxicity 10%, Side effects 8%, Portfolio 4%, Efficacy 33%. Kennedy T et al 1997 and Schuster D et al 2005 [5&6] has suggested that phase I clinical trial failures since pre-clinical ADME is due to pharmacokinetics 14%, Toxicity 43%, Efficacy 36%,Other 7%. These are not a new findings, and efforts have been made to automate and miniaturize methods to measure solubility, stability, Pka, bioavailability, brain penetration, hepatotoxicity and several other parameters.

Recent attention has focused on methods for early (in silico and in vitro) assessment of absorption and the need for similar tools in the ADMET arena has been recognized. Early methods for metabolism clearance and toxicity testing eliminate toxic compounds. The goal of early ADMET screening is to determine the properties of compound sets. The aim of early ADMET screening is to rank compounds for safety and drug like properties in parallel with potency ranking. This is the ADMET equivalent of structure activity relationships (SARs), also known as structure -toxicity relationships (STRs). So what are the drivers that will cause the process to change, and importantly, what will be technological enablers that can be applied to achieve transformation.

A scientist (Lipinski) of Pfizer has suggested/developed the rule of 5 [7]. This is an awareness tool (now used as screening tools) for medicinal chemists that suggest that there will be poor absorption if a molecule has two or more of the followings: more than 5 H-bond donors (HBD); a molecular weight (Molwt) >500; c log P> 5; the sum of Ns and Os (a rough measure of H- bond acceptors)>10. It is inherently costly to try to fix poor developability by formulation i.e. alternate way of formulations and delivery systems during the lead optimization phase.

Veber DF et al [8] draw conclusion for oral bioavailability measurements on the basis of 1100 drug candidates that oral bioavailability in rat is depends on total no of rotatable bond and polar surface area. They suggested compounds which meet only the two criteria of (1) 10 or fewer rotatable bonds and (2) polar surface area equal to or less than 140 A(2) (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailability in the rat. Kuentz MT and Arnold Y have studied molecular properties of lipophylic drugs for oral bioavailability. All these three generalization have added new insights in lead optimization.

Clinical trials: Early stages good decisions have profound effects on later costs. Clinical trials are the most expensive and time consuming, accounting for almost 40% expenditure. Clinical trials serves only to confirm finding of efficacy, bioavailability and safety as predicted in preclinical phases of development. In other words, early screening needs to be improved to avoid later failure.

Figure 3 current trend of drug development consists of target identification, target validation, hit identification (screening), , lead optimization combichem, preclinical development, clinical phase I, phase II and phase III and launch into market.

[1] DiMasi JA, Hansen RW, Grabowski HG. "The price of innovation: new estimates of drug development costs" J Health Econ., 22:2, 151-185, 2003.

[2] DiMasi JA, "The value of improving the productivity of the drug development process; faster time and better decisions" pharmacoeconomics, 20:3, 1-10, 2002.

[3] Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. "Definition and Antagonism of Histamine H2-receptors" Nature, 236: 385-390, 1972.

[4] Prentis RA, Lis Y, Walker SR."Pharmaceutical innovation by the seven UK-owned pharmaceutical companies 1964-1985" Br J Clin Pharmacol., 25,387-96, 1988.

[5] Kennedy T, "Managing the drug discovery/development interface" Drug Discov Today, 2: 436-44, 1997.

[6] Schuster D, Laggner C, Langer T, "Why drugs fail: a study on side effects in new chemical entities". Curr Pharm Des. 11:27, 3545-59, 2005.

[7] Lipinski CA, Lombardo F, Dominy BW, Feeney PJ."Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings" Adv Drug Deliv Rev., 46, 3-26, 2001.

[8]Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. "Molecular properties that influence the oral bioavailability of drug candidates". J Med Chem. 45:12, 2615-23,2002.

[9] Kuentz MT, Arnold Y. "Influence of molecular properties on oral bioavailability of lipophilic drugs - mapping of bulkiness and different measures of polarity". Pharm Dev Technol.,14(3),312-20, 2009.