Drug Discovery: A Complex and Time Consuming Aspect
Pharmaceutical Chemistry, Osmania University, Hyderabad, Telangana, India
- *Corresponding Author:
- Revathi B
M. Pharmacy, Pharmaceutical Chemistry,
Hyderabad, Telangana, India.
E-mail: [email protected]
Received: 15 March 2015 Revised: 20/05/2015 Accepted: 22 March 2015
Visit for more related articles at Research & Reviews in Pharmacy and Pharmaceutical Sciences
Drug discovery process is a complex and time consuming aspect. In olden days, the process begins with the selection of a synthesized or extracted molecule and screening it for various activities. Innovation does not mean to forget the classical drug discovery. In a developing country like India, every pharmaceutical industry cannot cop up with the novel technologies of drug discovery. Government is encouraging the companies to undertake the job of drug discovery by providing tax exemptions, sponsoring projects through CSIR, DBT, DST. Global companies are outsourcing about US$ 1billion to Indian CRO in the next 3-4 yrs. We may be replaced by China in the future just as we replaced European countries. World recognized Indian pharmaceutical industries to provide generic drugs but not recognized for innovations
Drug discovery, India, Global market, Drug screening, R&D, Revenue
Drug discovery process is a complex and time consuming aspect. In olden days, the process begins with the selection of a synthesized or extracted molecule and screening it for various activities. It is really a cumbersome job as thousands of molecules need to be screened for activity (Classical drug discovery process) [1-8]. India, regarding this aspect did not compete with the global countries due to poor knowledge, economic status and other reasons. We have to depend on other nations and hence making the drugs costlier. But by taking the advantage of process patent, we strived hard for the production of drugs. After 30 years, we are now in a position to manufacture drugs by ourselves and occupied 3rd position in the global market by exporting our drugs to other countries [9-21].
A revolutionary change has occurred globally in the process of discovery of new drug molecules by the advent of various sophisticated techniques like high throughput screening, robotics and computer simulations to minimize the time for the process of drug discovery. Neither the process is chemistry driven or technology driven. Rather it is the integration of both [22-34].
In the past, Investment of Indian companies in drug R&D is 0.6% of the turnover. Presently, pharma companies are spending 5% of turnover which increased 70 fold compared to 60s and 70s. The driving force behind R&D is obviously innovation. Innovation does not mean to forget the classical drug discovery. In a developing country like India, every pharmaceutical industry cannot cop up with the novel technologies of drug discovery [35-56]. Only Multinational companies can afford the cost of drug discovery. With the strong co-ordination between Industry and academics, even medium scale companies in a region should step into the drug discovery process utilizing classical methods. Further, Indian industry is largely concentrating upon development of new dosage forms or ANDA s rather than on discovery of new drug molecules which requires huge investments and no guarantee of profits [57-72].
Government is encouraging the companies to undertake the job of drug discovery by providing tax exemptions, sponsoring projects through CSIR, DBT, DST. It is the responsibility of industries and academics to utilize these benefits and step more into the ‘omic’ era (proteomics, genomics) along with other countries. Emerging technologies like stem cell research, dendritic vaccines which are likely to be commercially exploitable in the near future should not be neglected [73-85]. Biotechnology products are the future of R&D efforts world over and they are going to occupy 30% of R&D .
Regulatory bodies should also react as quickly as possible. They should assist the industries in the process and reduce the time for approving a drug molecule like in European countries. The time taken for an IND approval in USA is 1month whereas in India it is unpredictable. China became the first to approve the H1N1 vaccine but we have not initiated the trail at least. Similarly, DNA vaccine sponsored by the DBT is not moving forward as it completed phase-II in other countries [87-92].
Strong co-ordination between Industry, Academics and Regulatory authorities reduces the complexity in the process to some extent and encourages more and more companies to undertake the responsibility. In a report given by the organization Stratfer states that the development in India cannot be predicted in the next 10 years and no significant changes will occur. It also reports that India is very rich in resources but did not use them completely till now. There is also a need to create a strong bridge between traditional systems of medicine and pharmacy particularly with the area of drug discovery .
Risorine (Rifampicin+Isoniazid+Piperine) by Cadila pharmaceuticals is a classic example which utilized traditional medicine in which the dose of rifampicin and isoniazid is reduced by utilizing the enhancing bioavailability property of piperine extracted from peppers [94,95].
India is going to be a hub of clinical trials for other countries due to more population and less cost. Global companies are outsourcing about US$ 1billion to Indian CRO in the next 3-4 yrs. We may be replaced by China in the future just as we replaced European countries [96-98]. World recognized Indian pharmaceutical industries to provide generic drugs but not recognized for innovations. We have to provide also the patented products to world [99,100]. Let us utilize our own natural resources of traditional system of medicine, skilled work force and prove to the global market that we are not inferior to any other country in the process of drug discovery.
- Baig MH, Ahmad K, Adil M, Khan ZA, Khan MI, et al. (2015) Drug Discovery and In Silico Techniques: A Mini-Review. EnzEng 4:123. doi: 10.4172/2329-6674.1000123
- Miyaoka T, Kawano K, Furuya M, Wake R, Hashioka S, et al (2015) Efficacy and Safety of Sansoninto in Insomnia with Psychiatric Disorder: An Open-Label Study. AlternIntegr Med 4:181. doi: 10.4172/2327-5162.1000181
- Merad M, Soufi W, Ghalem S, Boukli F, Baig MH, et al. (2014). Molecular Interaction of Acetylcholinesterase with Carnosic Acid Derivatives: A Neuroinformatics Study. CNS & neurological disorders drug targets. 13(3), 440-446.
- Terstappen G, Reggiani A (2001). In silico research in drug discovery. Trends in pharmacological sciences 22(1): 23-26.
- Blake RA (2007). Target validation in drug discovery. Methods Molecular Biology 356:367-77.
- Ekins S, Freundlich JS, Hobrath JV, White EL, Reynolds RC (2014). Combining computational methods for hit to lead optimization in Mycobacterium tuberculosis drug discovery. Pharmaceutical research 31(2): 414-435.
- Smith C (2003) Drug target validation: Hitting the target. Nature 422: 341-345.
- Green DV, Segall M (2014). CHEMOINFORMATICS IN LEAD OPTIMIZATION. Chemoinformatics for Drug Discovery 149-178.
- Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2012) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews 64: 4-17.
- Vacca J P, Condra J H (1997) Clinicaly effective HIV-1 protease inhibitors. Drug Discovery Today 2: 261-72
- Baig MH, Shakil S, Khan AU (2012). Homology modeling and docking study of recent SHV type ÃŸ-lactamses with traditional and novel inhibitors: an in silico approach to combat problem of multiple drug resistance in various infections. Medicinal Chemistry Research 21(9): 2229-2237.
- Doman TN, McGovern SL, Witherbee BJ, Kasten TP, Kurumbail R, et al. (2002) Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. Journal of Medicinal Chemistry 45: 2213-2221.
- Danishuddin M, Khan A, Faheem M, Kalaiarasan P, Hassan Baig M, et al. (2013). Structure-based screening of inhibitors against KPC-2: designing potential drug candidates against multidrug-resistant bacteria. Journal of Biomolecular Structure and Dynamics 32(5):741-50
- Baig MH, Danishuddin M, Khan S, Khan AU. (2012). Screening of inhibitors for S130G inhibitor resistant mutants of TEM type beta-lactamase. Bioinformation 8(24): 1225.
- Laskowski RA, Hutchinson EG, Michie AD, Wallace AC, Jones ML, et al. (1997) PDBsum: a Web-based database of summaries and analyses of all PDB structures. Trends Biochemical Sciences 22: 488-490.
- Traxler P M (1997) Protein tyrosine kinase inhibitors in cancer treatment. Expert Opinion on Therapeutic Patents 7: 571-88.
- Brady SF, Stauffer KJ, Lumma WC, Smith GM, Ramjit HG, et al. (1998) Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy) prolyl trans-4-aminocyclohexylmethyl amide (L-372,460): coapplication of structure-based design and rapid multiple analogue synthesis on solid support. Journal of Medicinal Chemistry 41: 401-406.
- Abad VC, Guilleminault C (2005) Sleep and psychiatry.DialoguesClinNeurosci 7: 291-303.
- Tsuno N, Besset A, Ritchie K (2005) Sleep and depression.JClin Psychiatry 66: 1254-1269.
- Cohrs S (2008) Sleep disturbances in patients with schizophrenia : impact and effect of antipsychotics.CNS Drugs 22: 939-962.
- Mahfoud Y, Talih F, Streem D, Budur K (2009) Sleep disorders in substance abusers: how common are they?Psychiatry (Edgmont) 6: 38-42.
- Smith MT, Huang MI, Manber R (2005) Cognitive behavior therapy for chronic insomnia occurring within the context of medical and psychiatric disorders.ClinPsychol Rev 25: 559-592.
- Zammit GK, Weiner J, Damato N, Sillup GP, McMillan CA (1999) Quality of life in people with insomnia.Sleep 22 Suppl 2: S379-385.
- BÃ©langer L, Morin CM, Langlois F, Ladouceur R (2004) Insomnia and generalized anxiety disorder: effects of cognitive behavior therapy for gad on insomnia symptoms.J Anxiety Disord 18: 561-571.
- Riedel BW, Lichstein KL (2000) Insomnia and daytime functioning.Sleep Med Rev 4: 277-298.
- National Institutes of Health (2005) National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005.Sleep 28: 1049-1057.
- Drug target validation: Hitting the target. Nature 422: 341-345.
- Wang YC (1983) Hand book of Commonly Used Chinese Herbal Prescriptions, Oriental Healing Arts Institute, Long Beach CA.
- Ministry of Health (2006) Labour and Welfare, â€œThe Japanese Pharmacopeia, Fifteenth Edition (15th edn).
- Yi PL, Tsai CH, Chen YC, Chang FC (2007) Gamma-aminobutyric acid (GABA) receptor mediates suanzaorentang, a traditional Chinese herb remedy, -induced sleep alteration.J Biomed Sci 14: 285-297.
- Yi PL, Lin CP, Tsai CH, Lin JG, Chang FC (2007) The involvement of serotonin receptors in suanzaorentang-induced sleep alteration.J Biomed Sci 14: 829-840.
- Yang B, Zhang A, Sun H, Dong W, Yan G, et al. (2012) Metabolomic study of insomnia and intervention effects of suanzaoren decoction using ultra-performance liquid-chromatography/electrospray-ionization synapt high-definition mass spectrometry. J Pharm Biomed Anal 58: 113-124.
- Li Y, Liang X, Xiao H, Bi K (2003) Determination of spinosin in rat plasma by reversed-phase high-performance chromatography after oral administration of Suanzaorendecoction.JChromatogr B AnalytTechnol Biomed Life Sci 787: 421-425.
- Chen CY, Chen YF, Tsai HY (2008) What is the effective component in suanzaoren decoction for curing insomnia? Discovery by virtual screening and molecular dynamic simulation.JBiomolStructDyn 26: 57-64.
- American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders, revision (DSM-IV-TR)(4thedn), American Psychiatric Association, Washington DC.
- Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ (1989) The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research.Psychiatry Res 28: 193-213.
- Bastien CH, ValliÃ¨res A, Morin CM (2001) Validation of the Insomnia Severity Index as an outcome measure for insomnia research.Sleep Med 2: 297-307.
- Soldatos CR, Dikeos DG, Paparrigopoulos TJ (2000) Athens Insomnia Scale: validation of an instrument based on ICD-10 criteria.JPsychosom Res 48: 555-560.
- Guy W (1976) National Institute of Mental Health. CGI, Clinical Global Impression In ECDEU Assessment Manual for Psychopharmacology. revised Rockville MD: 534-537
- Inagaki A, Inada T (2006) Dose equivalence of psychiatric drugs. Jpn J ClinPsychopharmacol 9: 1443-1447.
- American Academy of Sleep Medicine (2005) International Classification of Sleep Disorders (2ndedn) Diagnostic and Coding Manual. American Academy of Sleep MedicineWestchesterIL
- Rickels K, Case WG, Schweizer EE, Swenson C, Fridman RB (1986) Low-dose dependence in chronic benzodiazepine users: a preliminary report on 119 patients.Psychopharmacol Bull 22: 407-415.
- Catena-Dell'Osso M, Marazziti D, Rotella F, Bellantuono C (2012) Emerging targets for the pharmacological treatment of depression: focus on melatonergicsystem.Curr Med Chem 19: 428-437.
- Saito K, Umeda S, Kawashima K, Kano Y (2000) Pharmacological properties of traditional medicines. XXVI. Effects of Sansohnin-to on pentobarbital sleep in stressed mice.Biol Pharm Bull 23: 76-79.
- WHO (2000) General guidelines for methodologies on research and evaluation of traditional medicines. Document: WHO/EDM/TRM/2000.1 Geneva, Switzerland.
- Nazem A, Mansoori GA (2011) Nanotechnology for Alzheimer's disease detection and treatment. Insciences J 1: 169-193.
- Nazem A, Mansoori GA (2014) Nanotechnology Building Blocks for Intervention with Alzheimer’s Disease Pathology: Implications in Disease Modifying Strategies. J Bioanal Biomed 6: 009-014.
- Cummings JL (2009) 'efinLnJ and labeling disease-modifying treatments for Alzheimer's disease. Alzheimers Dement 5: 406-418.
- Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M (2010) Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 9: 702-716.
- Sabbagh JJ, Kinney JW, Cummings JL (2013) Animal systems in the development of treatments for Alzheimer's disease: challenges, methods, and implications. Neurobiol Aging 34: 169-183.
- Castellani RJ, Perry G (2012) Pathogenesis and disease-modifying therapy in Alzheimer's disease: the flat line of progress. Arch Med Res 43: 694-698.
- Nazem A, Mansoori GA (2008) Nanotechnology solutions for Alzheimer's disease: advances in research tools, diagnostic methods and therapeutic agents. J Alzheimers Dis 13: 199-223.
- Dimasi JA (2001) New Drug Development in the United States from 1963-1999. ClinPharmacolTher 69: 286-296.
- Warren JB (2011) Drug discovery: lessons from evolution. Brit J ClinPharmaco 71: 497-503.
- Sleep and psychiatry.DialoguesClinNeurosci 7: 291-303.
- Rask-Andersen M, AlmÃ©n MS, SchiÃ¶th HB (2011) Trends in the exploitation of novel drug targets. Nat Rev Drug Discov 8: 549-590.
- Zhang XHD (2011) Optimal High-Throughput Screening: Practical Experimental Design and Data Analysis for Genome-scale RNAi Research. Cambridge University Press, New York.
- Schneider G, Fechner U (2005) Computer-based de novo design of drug-like molecules. Nat Rev Drug Discov 4: 649-663.
- Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70: 461-477.
- Robinson S, Delongeas JL, Donald E, Dreher D, Festag M, et al. (2008) A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development. RegulToxicolPharmacol 50: 345-352.
- Meadows M (2002) The FDAâ€™s Drug Review Process: Ensuring Drugs are Safe and Effective. FDA Consum 36: 19-24.
- McNeil JJ, Piccenna L, Ronaldson K, Ioannides-Demos LL (2010) The Value of Patient-Centred Registries in Phase IV Drug Surveillance. Pharm Med 24: 281â€“288.
- DiMasi JA, Hansen RW, Grabowski HG (2003) The Price of Innovation: New Estimates of Drug Development Costs. J Health Econ 22: 151-185.
- Adams CP, Brantner VV (2010) Spending on new drug development. Health Economics 19: 130-141.
- U.S. Department of Health and Human Services (2004) Innovation or Stagnation: Innovation or Stagnation? Challenge and Opportunity on the Critical Path to New Medical Products. Food and Drug Administration.
- Department of Health and Human Services (2003)Safety Reporting Requirements for Human Drug and Biological Products, Food and Drug Administration.
- Klepper MJ (2004) The periodic safety update report as a pharmacovigilance tool. Drug Safety 27: 569-578.
- Sleep and depression.JClin Psychiatry 66: 1254-1269.
- Ravindran S, Zharikova OL, Hill RA, Nanovskaya TN, Hankins GD, et al. (2006) Identification of glyburide metabolites formed by hepatic and placental microsomes of humans and baboons. BiochemPharmacol 72: 1730 - 1737.
- Ravindran S, Honrao C, Sahu R, Basu S, Basit A, et al. (2011) Determining quantity of metabolites without synthetic standards: An approach using LC-PDA-MS. International Journal of Chemical and Analytical Science 2: 1219-1221.
- Ravindran S, Honrao C, Sahu R, Basit A, Madireddy S, et al. (2011) Optimal use of mass spec scan modes to identify an unknown metabolite. Drug Invention Today 3: 259-261.
- Ravindran S, Basu S, Gorti SKK, Surve P, Sloka N (2012) Metabolic profile of glyburide in human liver microsomes using LC-DAD-Q-TRAP-MS/MS. Biomed Chromatogr
- Sleep disturbances in patients with schizophrenia : impact and effect of antipsychotics.CNS Drugs 22: 939-962.
- Burmester JK, Sedova M, Shapero MH, Mansfield E (2010) DMET microarray technology for pharmacogenomics-based personalized medicine. Methods MolBiol 632: 99-124.
- Sissung TM, English BC, Venzon D, Figg WD, Deeken JF (2010) Clinical pharmacology and pharmacogenetics in a genomics era: the DMET platform. Pharmacogenomics 11: 89-103.
- Hamid GA (2012) Targeted therapy in oncology: A key player in the move towards personalized medicine. J Develop Drugs 1.
- Dieras V, Bachelot T (2013) The success story of trastuzumabemtansine, a targeted therapy in HER2-positive breast cancer. Target Oncol.
- Wolf CR, Smith G, Smith RL (2000) Science, medicine, and the future: Pharmacogenetics. BMJ 320: 987-990.
- Roses AD (2000) Pharmacogenetics and future drug development and delivery. Lancet 355: 1358-1361.
- Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286: 487-491.
- Meyer UA (2000) Pharmacogenetics and adverse drug reactions. Lancet 356: 1667-1671.
- Goodsaid FM, Amur S, Aubrecht J, Burczynski ME, Carl K, et al. (2010) Voluntary exploratory data submissions to the US FDA and the EMA: experience and impact. Nat Rev Drug Discov 9: 435-445.
- Sakharkar MK, Sakharkar KR, Pervaiz S (2007) Druggability of human disease genes. Int J Biochem Cell Biol 39: 1156-1164.
- Sleep disorders in substance abusers: how common are they?Psychiatry (Edgmont) 6: 38-42.
- Cognitive behavior therapy for chronic insomnia occurring within the context of medical and psychiatric disorders.ClinPsychol Rev 25: 559-592.
- Quality of life in people with insomnia.Sleep 22 Suppl 2: S379-385.
- Insomnia and generalized anxiety disorder: effects of cognitive behavior therapy for gad on insomnia symptoms.J Anxiety Disord 18: 561-571.
- Insomnia and daytime functioning.Sleep Med Rev 4: 277-298.
- National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005.Sleep 28: 1049-1057.
- Klein DF (2008) The loss of serendipity in psychopharmacology. JAMA 299: 1063-1065.
- Kaitin KI (2008) Obstacles and opportunities in new drug development. ClinPharmacolTher 83: 210-212.
- Hsieh Y (2008) HPLC-MS/MS in drug metabolism and pharmacokinetic screening. Expert Opin Drug MetabToxicol 4: 93-101.
- Gamma-aminobutyric acid (GABA) receptor mediates suanzaorentang, a traditional Chinese herb remedy, -induced sleep alteration.J Biomed Sci 14: 285-297.
- The involvement of serotonin receptors in suanzaorentang-induced sleep alteration.J Biomed Sci 14: 829-840.
- Determination of spinosin in rat plasma by reversed-phase high-performance chromatography after oral administration of Suanzaorendecoction.JChromatogr B AnalytTechnol Biomed Life Sci 787: 421-425.
- Lee HS, Bae T, Lee JH, Kim DG, Oh YS, et al. (2012) Rational drug repositioning guided by an integrated pharmacological network of protein, disease and drug. BMC SystBiol 6: 80.
- Harrison C (2011) Signatures for drug repositioning. Nat Rev Genet 12: 668.
- Yang L, Agarwal P (2011) Systematic drug repositioning based on clinical side-effects. PLoS One 6: e28025.
- Jin G, Fu C, Zhao H, Cui K, Chang J, et al. (2012) A novel method of transcriptional response analysis to facilitate drug repositioning for cancer therapy. Cancer Res 72: 33-44.