Ariel Fernandez, Ariel Fernandez books, Ariel Fernandez Research, Ariel Fernandez Stigliano, Biochemistry, Biotechnology, Cancer Research, Dehydron, Drug design, Hasselmann Professor at Rice University, Journal of Clinical Investigation, National Institutes of Health, Physics at the Biomolecular Interface, Rice University, WaterMap

Ariel Fernandez’s Alternative “WaterMaps” of 2007 Look Much Like Precursors to WaterMap

Ariel Fernandez   Drug designers often implement molecular therapies to block malfunctioning proteins that are causing disease. They do so by creating small molecules that bind to the intended protein target when suitably delivered. The procedure has its risks as unintended targets (off-target proteins) may also be hit or impaired, especially when they are structurally similar (homologous) to the intended target. To achieve specificity and improve affinity for the intended target, practitioners in drug design often use WaterMap®, a product of the NY-based company Schrodinger. WaterMap is regarded by some as a gold standard in the field.

   What does WaterMap do? It identifies water molecules surrounding the protein target that may be easily removable as the purported drug binds to the target. Thus, a WaterMap of the target-water interface may provide the designer with valuable information to optimize a given drug lead. Since WaterMaps of homologous proteins are somewhat different, they may be used to tell apart homologs through selective molecular recognition. This much almost everyone knows…

   So, who pioneered these “WaterMaps”? One would assume Schrodinger scientists did, who else? Well, maybe they were not the first to get there. A similar method was published earlier and the Schrodinger folks may have not been aware of it. The facts as now described by Ariel Fernandez and Ridgway Scott in Trends in Biotechnology (2017) are that in May and December of 2007, Ariel Fernandez and coworkers published two papers on the local lability of interfacial water and contrasted the “dewetting propensity” patterns across protein targets to design anticancer drugs with controlled drug specificity. These papers are: Fernandez et al. Cancer Research, 2007, Priority Report, and Fernández, A., et al. (2007) Journal of Clinical Investigation 117:4044-4054. The former contains what Ariel Fernandez has named “local dewetting propensities” that surely look like precursors to WaterMap and were featured in the cover of Cancer Research for the May 1, 2007 issue. In December of 2007, in Figs 1-3 in Fernández, A. et al. (2007) Journal of Clinical Investigation 117:4044-4054, you may find the first “WaterMap” analysis of two proteins that needed to be differentiated through molecular recognition.

First "WaterMap" by Ariel Fernandez, probably a precursor to WaterMap.

First “WaterMap” by Ariel Fernandez, probably a precursor to WaterMap.

CANCER RESEARCH MAY 1, 2007 COVER LEGEND: Extensive exposure to molecular targeted therapy elicits mechanisms of drug resistance, typically promoting mutations in the protein target that lower the affinity for the drug inhibitor. Thus, protein kinases, the central targets for drug-based cancer treatment, avoid functional impairment by developing adaptive mutations. Redesigning a drug to target a drug-resistant mutant kinase constitutes a therapeutic challenge. Fernández et al. approach this problem by redesigning the anticancer drug imatinib guided by local changes in interfacial de-wetting propensities of the C-Kit kinase target introduced by an imatinib-resistant mutation. The ligand is redesigned by sculpting the shifting hydration patterns of the target, quantified by the bar plot in the figure. The association with the modified ligand overcomes the mutation-driven destabilization of the induced fit, as shown in the bottom molecular displays. Consequently, the redesigned drug inhibits both mutant and wild-type kinase. The modeling effort is validated through molecular dynamics, test tube kinetic assays of downstream phosphorylation activity, high-throughput bacteriophage-display kinase screening,cellular proliferation assays, and cellular immunoblots. The inhibitor redesign reported delineates a molecular engineering paradigm to impair routes for drug resistance. Inspired by these findings, Fernández et al. envision a strategy for drug redesign that “corners” mutation-induced adaptation, so that the only recourse to avoid drug-promoted inhibition becomes a mutation that renders the target protein functionally inactive. For details, see the article by Fernández et al.on page 4028 in this issue.

   Evidently, the method introduced by Ariel Fernandez and highlighted in the figure caption above is a precursor, possibly equivalent, to WaterMap.  And here is a “WaterMap” by Ariel Fernandez, dating back to 2007, used exactly as WaterMap is used:

WaterMap by Ariel Fernandez (J. Clin. Invest., 2007)

“WaterMap” by Ariel Fernandez dating back to 2007 (The Journal of Clinical Investigation 117, 4044-4054, 2007, reproduced with permission).

Furthermore, it is likely that a 3-body energy contribution described in Ariel Fernandez’s books has been omitted in the standard WaterMap analysis of “counterintuitive” desolvation sites. Usual computations of the reversible work to transfer interfacial water to the bulk do not take into account that, as water is displaced by a nonpolar group upon ligand binding, nearby preformed intramolecular hydrogen bonds that were previously exposed to solvent (dehydrons) become strengthened and more stable. Thus, the nonpolar group may be designed to displace water originally hydrating a polar group only if the latter is hydrogen bonded to another polar forming a dehydron. “Wrapping preformed hydrogen bonds” in this way stabilizes the drug-target complex, thereby enhancing affinity. This is a three-body effect (nonpolar with polar pair) that Ariel Fernandez named “wrapping interaction”.

 

Standard
Argentina, Ariel Fernandez, Ariel Fernandez book, Ariel Fernandez Publications, Ariel Fernandez Research, Dehydron, 阿列尔·费尔南德斯, Hasselmann Professor at Rice University, Joshua Cherry, Joshua L. Cherry, Joshua L. Cherry NIH, Michael Lynch, Nature, Nature Addenda, NIH, Republic of China, Rice University News, Sze-Bi Hsu, Taiwan, Tsing-Hua University, Wen-Hsiung Li

The Nature-Related Research by Ariel Fernandez at the Republic of China

“Residents and interns worked a lot of hours, and I wrote honestly about what it was like to be an intern. One of the deans wasn’t crazy about that. It reminded me that my core identity is as a journalist, constantly challenging things…Blogs are powerful and lower the publishing barrier.”
Ivan Oransky

This post constitutes a bit of a digression but a justified one since the research I intend to discuss served as the basis for a professional paper recently exposed by junk journalism (see our previous entry). Here I vindicate Professor Ariel Fernandez (阿列尔·费尔南德斯), the discoverer of the dehydron (脱水元) and a remarkably creative and imaginative physical chemist and mathematician -as attested by his publications– who recently had his share of spats with the blog-based junk journalism. I am specifically referring to the coverage of the so-called “post-publication peer review” of one of the doctor’s papers in Nature (see the previous post). This paper was challenged by Joshua Cherry, a person of unreported and unverified employment at NIH. Joshua Cherry corresponded extensively with Ariel Fernandez before deciding to operate hiding in anonymity once Dr. Fernandez alerted him that he needed to learn the subject before writing reviews. The blog-based type of journalism that covered the Nature story is completely unedited, not subject to scientific peer review and not subject to the most elementary standards of science. Driven by angry nobodies seeking notoriety, the Marcus-Oransky blog lies outside the scientific establishment, actually doing a disservice to science. Internet enables the exchange of information at unprecedented levels, but it also enables any person, however deranged, to pour his or her madness, and make it universally accessible without even having to disclose his or her identity. Fortunately, the majority of scientists do not take such journalism any more seriously that they would take a blog on the healing powers of the pyramids.

oransky fernandez
The source of the picture on the left is this article at Yale Medicince.

Dr. Ariel Fernandez is no stranger to Chinese audiences (Wikipedia Biosketch for Ariel Fernandez in Mandarin). I first became acquainted with him in 2008, when he delivered a lecture (poster and announcement below) at the Genomics Research Center in Academia Sinica, Republic of China. His host at the time was none other than Wen-Hsiung Li, the James Watson Professor at the University of Chicago and a towering figure in the field of molecular evolution. On that occasion, Ariel Fernandez lectured on the exploitation of evolutionary concepts to optimize drug design, an extremely original idea. The lecture introduced the key concept of dehydron, a sticky structural defect in proteins that is not conserved across homologous proteins. This lack of conservation makes dehydrons crucial selectivity filters for drug discovery, an idea later fleshed out in Ariel Fernandez’s first book “Transformative Concepts for Drug Design: Target Wrapping“. It was a mesmerizing lecture.

Ariel Fernandez lectures at Academia Sinica

Ariel Fernandez lecture announcement

Our second encounter took place in Hsinchu the next year, in 2009, when Ariel Fernandez began a series of visits to the National Tsing-Hua University sponsored in part by the Ministry of Education of the Republic of China (see illustration below). These visits hosted by Mathematics professor Sze-Bi Hsu led to the maturation of a revolutionary idea: introducing insights from structural biology into evolutionary biology, turning the latter more quantitative and precise. These thoughts eventually led to the Nature paper formerly coauthored by Michael Lynch. The seminal ideas by Ariel Fernandez at the National Tsing-Hua University, together with their ramifications in the field of aberrant aggregation-related disease, were enthusiastically reviewed at that institution, as shown in their “high-scope article” here.

Ariel Fernandez at Tsing-Hua University

Ironically, it was Michael Lynch who heralded these discoveries in auspicious terms. Thus, in 2009, Lynch had this to say to Rice University News and Media:
“One aspect of Ariel Fernandez’s research that is potentially groundbreaking is the observed tendency of proteins to evolve a more open structure in complex organisms”.
“This observation fits with the general theory that large organisms with relatively small population sizes — compared to microbes — are subject to the vagaries of random genetic drift and hence the accumulation of very mildly deleterious mutations”.

The liason of Ariel Fernandez with the Republic of China seems to be a long-lasting one. We are indeed fortunate that he has become a frequent visitor to the Mathematics Division at the National Center for Theoretical Science. His lecture last year is still announced here.

Taiwan lecture 1

It is not uncommon to see him announced on short notice, like in the poster below for an inpromptu lecture at Chiao Tung University on recent developments of the ideas he first brought to us at Academia Sinica five years earlier.

Ariel Fernandez Chiao Tung Univ

Dr. Fernandez, come back. We miss you!

RELATED READING:

Ariel Fernandez, Nature 474, 502-505 (2011)

Ariel Fernandez Innovation

Ariel Fernandez Consultancy

Wikipedia Biosketch of Ariel Fernandez in Mandarin

Ariel Fernandez featured in Baidu Encyclopedia (Mandarin)

Ariel Fernandez Scientist/Consultant

Ariel Fernandez Blog

Ariel Fernandez Book

Ariel Fernandez CV

Ariel Fernandez Google Scholar Citations

Ivan Oransky at Yale Medicine

Ariel Fernandez New Book (June 14, 2015)

 

Baidu 3

Ariel Fernandez featured in Baidu Encyclopedia.

 

RECENT COMMENTS (SEARCH UNDER COMMENTS)

LIPING says:
I love your inclusion of Oransky’s quote. In plain English it reads: SCIENCE IS HARD, TRASHING IT, AS WE DO AT RETRACTION WATCH, IS SO MUCH EASIER!
DECEMBER 6, 2014 AT 11:07 PM

WEISHI MENG says:
That is the translation, yes. Sad and tragic. It takes all kinds, I guess…
DECEMBER 6, 2014 AT 11:16 PM

TOBY says:
The towering Dr. Ariel Fernández is very good looking (was he photographed by El Greco or does he really share the build of a Mantis religiosa?), and Oransky is clearly a nasty bon viveur, jealous of the big man and who needs to start jogging if he wants to compete in the same scientific and glamorous world as our hero.
Also Oransky, learn one thing: one always has a better side for the pictures. Discover which one is yours and use it in all photos. Learn something from the aristos you good for nothing former headshrink!
DECEMBER 9, 2014 AT 1:38 PM

Standard