STRUCTURE-BASED DRUG DESIGN, that is the engineering of therapeutic ligands guided by the structure of the target proteins, has met a modest degree of success so far. Part of the problem relates to the difficulty in incorporating induced folding, the unpredictable structural adaptation of the target protein to the drug upon association. The mere existence of induced folding implies that structure-based drug design cannot be based on the current static picture but must necessarily incorporate dynamic features in most cases (Ariel Fernandez, Christopher Fraser and Ridgway Scott, Trends in Biotechnology 30, 1-7 (2012)). This makes the design problem quite daunting, especially when we consider that the induced folding problem is probably as hard as the protein folding problem, if not harder.

Even in the absence of dynamic guidance to drug design, there are a few “hard facts” that have been incorporated into the analysis. One of them is the usually accepted decrease in conformational entropy upon formation of the drug-target complex. This decrease in entropy is associated with the induced folding and obviously decreases the drug affinity since it is complex-destabilizing. However, upon examination of drug-target complexes reported in the Protein Data Bank, we found significant local mismatches across the drug-target interface, implying that induced unfolding was also possible upon association, and almost as likely to occur as induced folding! Invariably, the drugs that generated such induced unfolding were not the result of rational design but arose from the optimization of leads discovered via high-throughput screening. This is understandable since most designers have little or no command of entropy-based molecular engineering.

The induced unfolding of the target protein may appear quite striking and even counterintuitive to the unprepared mind. Yet, further reflection on the problem suggests that an entropy boost upon association can enhance affinity, as it decreases the free energy content of the complex. However, we are not yet prepared to incorporate purposely engineered drug-target mismatches into the designs. This is mainly because we are as incapable of controlling induced unfolding as we are of controlling induced folding. Entropy remains the bête noir of rational design.

Rather than placing these counterintuitive features under the rug, we need to bring them to broad daylight if we are ever to succeed at rational drug design.

Ariel Fernandez

Representative publications by the author:

Ariel Fernandez: “Almost-Split Sequences and Morita-Duality”.
Bulletin des Sciences Mathematiques. 2e series 110, 425-438 (1986).

Ariel Fernández and Harold A. Scheraga: “Insufficiently dehydrated hydrogen bonds as determinants for protein interactions”. Proceedings of the National Academy of Sciences, USA 100, 113-118 (2003).

Ariel Fernández and Ridgway Scott: “Adherence of packing defects in soluble proteins.” Physical Review Letters 91, 018102 (2003).

Ariel Fernández: “Keeping Dry and Crossing Membranes.” Nature Biotechnology 22, 1081-1084 (2004).

Ariel Fernández, et al.: “An anticancer C-kit kinase inhibitor is re-engineered to make it more active and less cardiotoxic”. Journal of Clinical Investigation 117, 4044-4054 (2007). (featured in Press Releases).

Ariel Fernández, Soledad Bazán and Jianping Chen: “Taming the induced folding of drug-targeted kinases”. Trends in Pharmacological Sciences 30, 66-71 (2009).

Ariel Fernández and Jianping Chen: “Human capacitance to dosage imbalance: Coping with inefficient selection”. Genome Research 19, 2185-2192 (2009).

Ariel Fernández and R. Stephen Berry: “Golden rule for buttressing vulnerable soluble proteins”. Journal of Proteome Research (ACS) 9, 2643-2648 (2010).

Ariel Fernández and Michael Lynch: “Nonadaptive origins of interactome complexity”. Nature 474, 502-505 (2011).

Ariel Fernández, Christopher Fraser and L. Ridgway Scott: “Purposely engineered drug-target mismatches for entropy-based drug optimization”. Trends in Biotechnology 30, 1-7 (2012).

Ariel Fernández: “Epistructural tension promotes protein associations”.
Physical Review Letters 108, 188102 (2012).

Ariel Fernández Stigliano: “Breakdown of the Debye polarization ansatz at protein-water interfaces”. Journal of Chemical Physics 138, 225103 (2013).

Ariel Fernández: “The principle of minimal episteric distortion of the water matrix and its steering role in protein folding”. Journal of Chemical Physics 139, 085101 (2013).

Ariel Fernández: “Transformative Concepts for Drug Design: Target Wrapping”. Springer, Heidelberg, Berlin (2010).

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