Angewandte rcatnmcniofct cukemia(CML).imatinib Advancing the Drug Design and Development drug is eof the d er typ ery and opmer ery.Ne ork phar and .the o this argeting for of disea hat paradoxical affai and bi ld be de all of th inform on st organic synt enot an the p plan s for al.To h nt n ures t dru ich n ng or ted hat try molecule (no mpr nts in al dru 550. logP be een 3. 5.5.and TPSA of 60-90A ent and in the ral op use ron atic system ring (with Thus ngther in lubilizins uch as m .computat hrough in le would ha nost likel aio ction step st d The latter a c nding nd valid It is impr nd ph mnd and more predictiv to their dr covery effor s.matchi acilitated by the ever- creasing power of computer And y for m eimer's and types of cancer re (Le 00g speed)shoul un dertake the challenge of improving even further the drug like as they attemnt to carrv their respective task d ery and d nd bi logica targe 山gan strategic initiatives that could bring within reach cures for MMPs) bionmkenahdbioiogeaiasayseoudpg 9132 www.angewandte.org 914treatment of chronic myelogenous leukemia (CML), imatinib was later found to bind to several kinases. Another impressive example of a multikinase inhibitor drug is sorafenib (Nexavar, Bayer). Approved by the FDA in 2005 for the treatment of advanced renal cell carcinoma, this drug is now employed for a number of other cancer types. This approach of multitarget drug mechanism of action is becoming a new paradigm in drug discovery. Network pharmacology and polypharmacol￾ogy,[40, 41] two relatively new directions in biomedical research, aim at understanding and exploiting this new strategy of molecular targeting for the treatment of disease.[6] The overarching new paradigm of both small-molecule drugs and biologics aims at more targeted strategies to cure disease without collateral damage that often leads to undesired side effects due to off-target promiscuity. Despite all of the new information on structural motifs and the properties they impart, and technological advantages in organic synthesis, the drug discovery and development process still fails to realize gains in the number of drug candidates successfully crossing the finish line of clinical trials and approval. To be fair to the medicinal chemists, we should note that drug candidates fail not only due to deficiencies in their molecular structures but also, and most importantly, because of lack of full understanding of the pathogenesis and biology of the disease. It has been estimated that, on average, 10 000 compounds are synthesized and tested before one of them makes it to the clinic as an approved drug. It is also interesting to note that analyses of several databases suggest that a “typical” medicinal chemistry molecule (not necessarily an actual molecule)[13] has a molecular weight in the range of 350–550, log P between 3.5–5.5, and TPSA of 60–90 2 ; it possesses 0–2 chiral centers, 30–50% of its carbon atoms are in the sp3 configuration, and it contains a biaryl bond linking a fused aromatic system and another ring (with one of the rings being a benzenoid). The typical molecule is also likely to contain a “solubilizing” group such as morpholine or piper￾azine bridged through a linker to an aryl ring, an amide, and an aromatic ring carrying a fluoride or chloride residue. This “typical” molecule would have most likely been synthesized in four to six steps that included an amide bond formation, a deprotection step (most probably a Boc removal from a structural motif introduced from a commercially available building block), and a palladium-catalyzed cross-coupling reaction (most likely a Suzuki reaction).[13] It is also of interest that the average potency of approved drugs is around 20 nm. Synthetic organic chemists have made impressive strides in their science and medicinal chemists have performed admirably in applying some of the emerging technologies in organic synthesis to their drug discovery efforts, matching the enormous advances made by biologists and clinicians in their domains. And yet a number of menacing diseases such as Alzheimers and certain types of cancer remain untreatable. To be sure, scientists and clinicians are capable and poised to undertake the challenge of improving even further the drug discovery and development process by systematic diagnostic and corrective actions through collaborative efforts and new strategic initiatives that could bring within reach cures for some of the remaining intransigent diseases. 3. Advancing the Drug Design and Development Process As convincingly argued by medicinal chemists and other pharmaceutical experts, the art and science of the drug discovery and development process needs changes and new paradigms.[4–24] However, due to the immense complexity of the drug discovery process, the response to this challenge can only be slow, under current conditions, despite the issues and uncertainties associated with the pharmaceutical industry. This somewhat paradoxical state of affairs becomes even more puzzling if we consider the modern instrumentation and technologies that could be deployed to address the remaining challenges. These sharp tools and powerful technologies include computer power and computational methods, chem￾bioinformatics, organic synthesis, genomics, biological assays, animal models (when appropriately predictive), and cognitive science. Among the possible explanations for this slow, rather than decisive move toward new paradigms of drug discovery and development, the more likely reasons are perhaps the current pressures to deliver drug candidates in shorter and shorter times, considerations of cost in manufacturing the drug if approved (which provides resistance to employ costly materials and modern synthetic technologies), and lack of appreciation of the enormous long-term medical and eco￾nomic benefits to be derived from such improvements (a phenomenon that leads, in turn, to favoring instead short￾term and temporary gains). Improvements in the classical drug discovery and devel￾opment process (see Figure 3, center; main pipeline indicated by red arrow) may come from recent and pending advances in chembioinformatics, computational methods and computer modeling (Figure 3, top), and chemistry and biology (Fig￾ure 3, bottom). Thus, strengthening and encouraging integra￾tion of intelligence gathering and processing using modern computer power, computational methods, cognitive science, and continuously updated databanks could provide a major boost to the theoretical and chembioinformatics components of the drug discovery and development process, while major innovations may be derived from modern chemical, biolog￾ical, and pharmacological developments. The latter should include a better understanding and validation of biological targets,[42] epigenetics,[43] diagnostic biomarkers, and clinical endpoints, new and improved biological and pharmacological in vitro and in vivo assays, wider applications of modern organic synthesis strategies and methods, novel structural motifs[44–46] and compound libraries, and more predictive early-phase clinical trials. Facilitated by the ever-increasing power of computers, computational methods and cognitive science, continuously updated databanks, and useful programs for mining them rapidly (i.e., “google-like” efficiency and speed) should become routine and accessible to biologists and chemists alike as they attempt to carry out their respective tasks. Databanks of biological targets and biological target–ligand matched pairs (TLMPs), matching molecular pairs (MMPs),[32–36] biomarkers, and biological assays could provide crucial intelligence and assistance for the target identification and validation and lead identification and optimization Angewandte . Essays 9132 www.angewandte.org 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2014, 53, 9128 – 9140