A Pursuit of Smart Chemistry Tackling Complex Biology by Way of Inventive Drug Design
Tomi K. Sawyer · Chemical Biology & Drug Design · 2009
What I see in Nature is a magnificent structure that we can comprehend only very imperfectly, and that must fill a thinking person with a feeling of humility. This is a genuinely religious feeling that has nothing to do with mysticism. (A. Einstein) The above quote of Albert Einstein provides an interesting prelude to the extraordinary scientific pursuit of novel medicines via smart drug discovery efforts that leverage a wealth of knowledge, innovative technologies and the human spirit for risk taking, creative insights, relentless resolve, goal-oriented focus, interdisciplinary team work and some good luck. Perhaps, we can take a lesson from Albert Einstein by way of inventive theoretical physics that he pondered, evaluated and ultimately transformed our way of thinking. The multidimensional nature of life processes and those aberrant changes underlying disease are now becoming well recognized as we further strive to take a systematic approach to tackling complex biology through identifying, validating and deciphering all therapeutic targets and pathways to envisage a comprehensive dynamic manifestation of the human genome (1-11). From a drug discovery perspective, there exists the proverbial race for breakthrough medicines (12), and new strategic approaches to advance novel modalities of drugs have been engaged, ranging from structural biology to chemical genetics, combinatorial libraries, molecular modelling of ligand–target interactions (e.g. virtual screening, pharmacophore mapping and de novo drug design) and emerging molecular informatics databases (13-27). Nevertheless, albeit with some exceptions, a single drug will unlikely be a cure, but it can nevertheless be a powerful component of the molecular armamentarium to combat life threatening and debilitating diseases. So, what is on the horizon with respect to tackling complex biology relative to smart chemistry? Perhaps, it is simply thinking differently. At a recent ACS Pharma Leaders meeting that I had the opportunity to participate and share my perspectives relative to breakthrough drug discovery on stapled helical peptides at Aileron Therapeutics (27), the prevailing view for the future was that scientists needed to explore more deeply into ‘drug space’ and not be constrained by dogmas or rules that limit the possibility for novel molecules (whether synthetic or biologic). Surprisingly (or not), small molecules that do not obey the rule-of-five are gaining momentum with examples already in the market place and with others advancing through preclinical/clinical studies. Peptides, a superclass of drugs in context of receptor and enzyme targets, vaccines and molecular frameworks to design second-generation peptidomimetics for a plethora of intracellular targets are back in vogue. In particular, the so-called ‘undruggable’ targets, including protein–protein interactions (e.g. transcription factors), are being aggressively sought, and a new era in smart drug discovery is at-hand (28-30). Relative to the so-called druggable genome to polypharmacology, our understanding of chemical and biological space is transcending from vast collections of experimental data points to an evolution of varying types of molecular informatics tools which will enable, guide and, with a bit of fortuity, predict the next generation of medicines. A renaissance of interest in what may be termed ‘non-classic’ drug discovery (i.e. beyond traditional small molecules) for many pharmaceutical and biotechnology companies is reflecting a major strategy to bolster R&D pipelines and tackle complex diseases with a robust repertoire of synthetic and biological molecules. Peptides, proteins, nucleic acids and natural products are key ingredients in such an expanded diversity of novel molecules for drug discovery. Finally, inventive drug design transcends the scientific process to that of the human spirit, and it further requires a positive working environment that will inspire individual creativity, multidisciplinary teamwork and transformational leadership (31, 32). These are the key elements to the modus operandi of creating breakthrough medicines as drug discovery scientists take action with unwavering urgency and purposeful perseverance. With respect to this Editorial, and as we each step into 2010, I would like to take the opportunity to wish you success as you strive to test new concepts, develop new methods and forge new understandings in your field of study. May your good works make a difference in this world that we share together. A SPECIAL INVITATION: I invite you to consider Chemical Biology & Drug Design (CB&DD) for submitting your outstanding research. As Editor-in-Chief of CB&DD, I am personally committed to the journal’s dedication to advance innovative science, technology and medicine by promoting multidisciplinary chemical biology and drug design (33). The scope of manuscript types includes Research Articles, Research Letters, Reviews, Perspectives, R&D Tutorials, R&D Highlights, Science Philosophy, Medicine Pipeline, Technology Platform, Words of Wisdom, Editorials, Commentaries and a Who’s Who in Chemical Biology and Drug Design. I welcome you to visit the journal website (http://www.cbdd.org).