Structure-Based Drug Design (SBDD): How proteins are the cornucopia of medicinal chemistry | Adamas University

Structure-Based Drug Design (SBDD): How proteins are the cornucopia of medicinal chemistry

Adamas University Pharmacy

Structure-Based Drug Design (SBDD): How proteins are the cornucopia of medicinal chemistry

Medicinal Chemistry is a subject that might sound elusive even to a number of graduate laypersons. While the name itself is quite lucid, a chemistry related to medicine, a few thoughts later, it can be quite confusing as well. Is it a specialized field of organic chemistry? Or does it deal with biochemistry? Why would a person require to study or specialize into such field? These questions are rational and may come to the mind even to a young pharmacy freshman year student. The subject is basically a wonderful and eclectic blend of all the subject mentioned above and much more. It has organic chemistry, biochemistry, physical chemistry, quantum chemistry and a great amount of mathematic and computation that qualified and experienced medicinal chemists may conjure up from their sleeves to address the conundrums of human health.

The discovery of drug is a tedious process that involves a great number of resources involved. While the core brunches of chemistry focuses on the novelty and science of a method/ process, medicinal chemistry focuses a lot more on the out come of the research. Therefore, not only science, the other aspect of technology such as process optimization and cost reduction are important focus for them. Medicinal chemists prepare and/or select appropriate compounds for biological evaluation that, if found to be active, could serve as LEAD COMPOUNDS. They then evaluate the STRUCTURE–ACTIVITY RELATIONSHIPS (SARs) of analogous compounds with regard to their in vitro and in vivo efficacy and safety. Today, medicinal chemists who are engaged in drug discovery are part of interdisciplinary teams, and must therefore understand not only the field of organic chemistry, but also a range of other disciplines to anticipate problems and interpret developments to help move the project forward.A more recent approach to this technique is using QSAR or Quantitative SAR, where manual exploration of SAR is replaced with computer based studies and also with seeming unrelated compounds. These studies can help explore physio-chemical properties of drugs that was previously impossible to explore.

The modern medicinal chemist, although part of a team, has a particularly crucial role in the early phases of drug discovery. The chemist, trained to prepare new chemicals and with an acquired knowledge of the target disease and of competitive drug therapies, has an important part in framing the hypothesis for the new drug project, which then sets the objectives for the project. The chemist also helps to decide which existing chemicals to screen for a lead compound and which screening hits need to be re-synthesized for biological evaluation. Purification and proper characterization of the new chemicals is also the responsibility of the chemist. When an in vitro ‘HIT’ is identified, the chemist decides on what analogous compounds should be obtained or synthesized to explore the SARs for the structural family of compounds in an effort to maximize the desired activity. Developing in vivo activity for the hit compound in an appropriate animal model is also mainly the responsibility of the chemist. This can often be one of the most difficult steps to accomplish because several factors, such as absorbability, distribution in vivo, rate of metabolism and rate of excretion (ADME), all present hurdles for the chemist to solve in the design and preparation of new, analogous chemicals for testing. The goal at this stage is to maximize efficacy while minimizing side effects in an animal model.

Structure-based drug design is one of several methods in the rational drug design toolbox. This time of drug designing strategies differ significantly from the a ligand based drug design where a particular target or structure of the protein is unknown and the only way is to explore is through the activity profile of the ligands or the small molecules. Drug targets are typically key molecules involved in a specific metabolic or cell signaling pathway that is known, or believed, to be related to a particular disease state. Drug targets are most often proteins and enzymes in these pathways. Drug compounds are designed to inhibit, restore or otherwise modify the structure and behaviour of disease-related proteins and enzymes. SBDD uses the known 3D geometrical shape or structure of proteins to assist in the development of new drug compounds. The 3D structure of protein targets is most often derived from x-ray crystallography or nuclear magnetic resonance (NMR) techniques. X-ray and NMR methods can resolve the structure of proteins to a resolution of a few angstroms (about 500,000 times smaller than the diameter of a human hair). At this level of resolution, researchers can precisely examine the interactions between atoms in protein targets and atoms in potential drug compounds that bind to the proteins. This ability to work at high resolution with both proteins and drug compounds makes SBDD one of the most powerful methods in drug design.The beauty of the SBDD method is the extremely high level of detail that it reveals about how drug compounds and their protein targets interact.

Docking Ligands: One of the key benefits of SBDD methods is the exceptional capability it provides for docking putative drug compounds (ligands) in the active site of target proteins. Most proteins contain pockets, cavities, surface depressions and other geometrical regions where small-molecule compounds can easily bind. With high-resolution x-ray and NMR structures for proteins and ligands, researchers can show precisely how ligands orient themselves in protein active sites. Open source bioinformatics tools such as VMD and NAMD, for example, help scientists examine multiple binding poses to determine which orientation is most likely to occur.

Furthermore, it’s well known that proteins are often flexible molecules that adjust their shape to accommodate bound ligands. In a process called molecular dynamics, SBDD allows researchers to dock ligands into protein active sites and then visualize how much movement occurs in amino acid side chains during the docking process. In some cases, there is almost no movement at all (i.e., rigid-body docking); in other cases, such as with the HIV-1 protease enzyme, there is substantial movement. Flexible docking can have profound implications for designing small-molecule ligands so this is an important feature in SBDD methods.

Lead Optimization: After a number of lead compounds have been found, SBDD techniques are especially effective in refining their 3D structures to improve binding to protein active sites, a process known as lead optimization. In lead optimization researchers systematically modify the structure of the lead compound, docking each specific configuration of a drug compound in a protein’s active site, and then testing how well each configuration binds to the site. In a common lead optimization method known as bioisosteric replacement, specific functional groups in a ligand are substituted for other groups to improve the binding characteristics of the ligand. With SBDD researchers can examine the various bioisosteres and their docking configurations, choosing only those that bind well in the active site. A few examples of bioinformatics tools that aid in lead optimization efforts are BIOSTER, WABE, and ClassPharmer Suite.

Alexander Fleming discovered penicillin out of serendipity. Clinical trials did not exist even 40 years ago. While discovery and official sanction of drugs were much easier process back in the previous century, those have resulted into diabolical outcomes as well which we may see with use of thiazides and teratogenicity. Therefore, the responsibility of the medicinal chemistry is not only to find an ‘effective’ drug but to provide a ‘safe and effective’ medicine. Thus, with the advancement of biotechnology drug discovery hasbeen taken to newer dimensions, a challenge that medicinal chemists embraces with arms wide open.

For further information about SBDD please see the following references –

1) Wang R,GaoY,Lai L (2000). “LigBuilder: A Multi-Purpose Program for Structure-Based Drug Design”. Journal of  Molecular Modeling 6 (7–8): 498–516.

2) Verlinde CL, Hol WG (July 1994). “Structure-based drug design: progress, results and challenges”. Structure 2 (7): 577–87.

3) Tollenaere JP (April 1996). “The role of structure-based ligand design and molecular modelling in drug discovery”. Pharm World Sci 18 (2): 56–62.

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