In April 2014 I took a permanent position.  I still had a few clients and I worked with them through the end of the year.  The end of the year also brought the end of my 23-year-old marriage.  Many more changes some I shouldn’t talk about some I wont talk about and some I will.
 
What’s different:

1. I’ve met the love of my life, a similarly recently divorced woman with Multiple Sclerosis.
2. We have lost three of our long-time companions, Biggles, Scout and Peanut, and gained a new one, Crash the Wonder Dog
3. My best friend, who I have know since age 12 and was the brother nature deprived me of, passed untimely of a very rare cancer, large cell neuroendocrine cancer of the colon.
4. My cluster headaches have returned after a 15-year remission and lead to a battle to stabilize it.

What’s the same:

1. I still believe small molecules are the most efficient method to treat disease
2. I still think CDD Vault is the best collaborative data management system available in the pharmaceutical industry
3. I still believe strongly in 3D QSAR and think CRESSET has the market locked up.

So what am I doing back.  I will be blogging more regularly now.  I also was to say if you are a 501-C3 looking for some computational support, or a small startup with people working for minimum wage, subsisting or trying to get SBIR grants, I am the kind of consultant you are looking for.  As long as there is not a conflict of interest with what I am doing for my employer, I am interested in pro bono or innovative remuneration schemes.  You probably can’t afford to hire me.  So, do let that worry you.  I have my own personal suite of software and I can bring it to bear on your problems, at the low, low cost of free, if you can interest me in the project.  I am particularly interested in demyelinating diseases, drug resistant infectious diseases and neglected tropical diseases.  Send me and email!

My maternal grandfather died of tuberculosis. He contracted it while serving in the First World War. He returned from France to live a life of diminished quality, shortened by an early death.  I can also remember, when I was a small child, in the 1970’s going for rides through Los Angeles’ Elysian Park area and passing what was then the Barlow Sanatorium. I asked my dad what a sanatorium was and was introduced at a young age to, what was still then, the isolating treatment of tuberculosis.  The Barlow Sanatorium is now the Barlow Respiratory Hospital. Los Angeles, fortunately, no longer has the need for a facility dedicated to the treatment of TB.

My wife always tests positive with the Mantoux tuberculin skin test, the most common screening test for TB.  She grew up in Kenya and was most likely exposed when she was young sufficiently to produce an antibody response without being infected.   False positives in the Mantoux test are fairly common, leading to chest X-rays and sputum cultures being truly diagnostic. So I have had an unusually significant number of interactions with TB for a first world citizen.

TB has certainly been around since 9000 BC and probably became a human disease as a consequence of the domestication of cattle.  Evidence has been found in Egyptian mummies from circa 3000 BC.  TB has been a scourge of humanity for all this time.  The death toll peaked in the 18th century when accounted for ~25% of all fatalities.  The advent of the sanitarium movement followed by modern antibiotics with the discovery of streptomycin in 1946 made total eradication of TB seem like an obtainable goal.  Then in the 1980’s the first drug resistant isolates were found, and we returned to the old days of an untreatable TB.

Since 1980 reported cases of tuberculosis have been rising steadily from 1,000,000/year to over 5,000,000/ year .  Approximately 1/3 of the world’s population is infected, and 3.7% of new and 20% reinfections involve some form of drug resistance.  Total drug resistant TB has been found in Italy, India and Iran. It is unclear how extensive this strain is.  Only 9% of TB cases are drug tested worldwide, making the extent of the problem largely unknown. 

You humble author was down with the flu last week.  What annoyed him tremendously is that he got his vaccination last October.  Also about the time the fever began to subside I started to get depressed.  I've been melancholy since then.  In the back of my mind, I remembered an association between influenza infection and mild to moderate depression lasting several weeks post morbidity. 

A little PubMed time led me to this paper in the Journal of Affective Disorders " Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts.", from whence the quote below comes.
"Seropositivity for influenza A (p=0.004), B (p<0.0001) and coronaviruses (p<0.0001) were associated with history of mood disorders but not with the specific diagnosis of unipolar or bipolar depression. Seropositivity for influenza B was significantly associated with a history of suicide attempt (p=0.001) and history of psychotic symptoms (p=0.005).'


So my personal observations have some basis in fact.  My mind wandered to Encephalitis Lethargica, (EL) which if you recall, followed in the wake of the Spanish Flu outbreak at the end of World War One (the centennial of the commencement of which is this year).  The cause of EL still is subject to debate; however, many studies have found antibodies to the basal ganglia in EL patients.  This seems to point to an autoimmune origin, triggered by Spanish flu infection perhaps? That particular strain of the flu was noted to cause a severe cytokine storm reaction.  Could this set people up for a later neurological autoimmune disease? 

The most common estimate of the number of viruses in the world is 10^31.  That is an astronomical number.  With that many viruses, I often wonder how many fluctuations in our physical well being could have an infectious cause.  How often do you wake up feeling a bit under the weather, but never bad enough to warrant a visit to the doctor.  No one is going to go to the effort to hunt a virus for "the blahs".  


Well, enough hypothesizing. I better get back to science that pays!

In a rapidly changing environment, it is very difficult to keep up with the latest trends.  Victrix understands this and is ready to help.  We have a four step solution.  We will help your web presence provide useful information to customers to drive them to your site.  We will manage your social media presence and use the tools to engage your potential customers and educate them about your products and services.  We will research specific potential clients/customers and begin a dialogue on their specific work.  This is much more effective than cold calling or visiting the same customer over and over again.  Finally we will put you into personal contact with people who genuinely need, want and are ready to buy.  This is the Victrix difference. 

These days there are more metrics that a supposed to lead you to the legendary "sweet spot" where all noble and pure drugs dwell than you can shake a stick at. The question arises: how many of them are actually useful as guides to drug optimization? A recent paper in Bioorganic & Medicinal Chemistry Letters tries to take a stab at assessing the usefulness of various composite parameter (ligand efficiency is probably the most commonly sighted species of said descriptor.)  

This is a quote from the paper that I find impressive.  Mainly that the author took such pains to track down all of the metrics and provide references.  I am much more lazy than the author, so you will have to read the paper to track down the references.  I will merely  provide the quote:

"Approximately 15 years ago Lipinski et al. published their seminal work linking molecular properties with oral absorption.1Since this ‘Big Bang’ of physical property analysis, the universe of parameters, rules and optimization metrics has been expanding at an ever increasing rate (Figure 1).2 Relationships with molecular weight (MW), lipophilicity,3 and 4 ionization state,5 pKa, molecular volume and total polar surface area have been examined.6 Aromatic rings,7 and 8 oxygen atoms, nitrogen atoms, sp3 carbon atoms,9 chiral atoms,9 non-hydrogen atoms, aromatic versus non-hydrogen atoms,10 aromatic atoms minus sp3 carbon atoms,6 and 11 hydrogen bond donors, hydrogen bond acceptors and rotatable bonds12 have been counted and correlated.13 In addition to the rules of five came the rules of 4/40014 and 3/75.15 Medicinal chemists can choose from composite parameters (or efficiency indices) such as ligand efficiency (LE),16 group efficiency (GE), lipophilic efficiency/lipophilic ligand efficiency (LipE17/LLE),18 ligand lipophilicity index (LLEAT),19 ligand efficiency dependent lipophilicity (LELP), fit quality scaled ligand efficiency (LE_scale),20 percentage efficiency index (PEI),21 size independent ligand efficiency (SILE), binding efficiency index (BEI) or surface binding efficiency index (SEI)22 and composite parameters are even now being used in combination.23 Efficiency of binding kinetics has recently been introduced.24 A new trend of anthropomorphizing molecular optimization has occurred as molecular ‘addictions’ and ‘obesity’ have been identified.25 To help medicinal chemists there are guideposts,21 rules of thumb,14 and 26 a property forecast index,27 graphical representations of properties28 such as efficiency maps, atlases,29 ChemGPS,30 traffic lights,31radar plots,32 Craig plots,33 flower plots,34 egg plots,35 time series plots,36 oral bioavailability graphs,37 face diagrams,28spider diagrams,38 the golden triangle39 and the golden ratio.40"


I personally have been a moderate advocate of the "Property Inquisition" method of drug discovery, finding it most useful in the selecting which hits to follow up on, rather than as a strict guide as to what to make and not to make. I have worked at companies where absolutely no attention was paid to any metric and others where chemists who made a compounds that violated the rules were publically shamed, even if they needed the compound as an SAR point.  I am interested in your experiences, dear readers.  Have you found any metric useful or particularly un-useful? Comment below, I would like to get the discussion started.  

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Since the Labor Day weekend marks the turn of the year from the light hearted playfulness of summer to a return to the routine of school and work, I thought a glimpse into the past of your humble author would be of, at least, marginal interest to you, gentle readers.  The photograph you see is me in high school.  I went to Glendora High School, in Glendora, California.  since my 30th reunion is approaching, I must admit it was 30 years ago.

In school, I was serious and studious.  I was a Valedictorian (we actually had 7) graduating with a 4.0 GPA (back then, there were no extra points for honors or AP classes). I was pathologically afraid of missing any points. I would study until I was so exhausted that I would get sick on vacations.  I never actually relaxed.  My one relief was playing Dungeons and Dragons with my small circle of close friends.  

College was easy in that I did well in all of my classes, but difficult in that I studied more than was necessary, had few friends and was very socially awkward.  I actually hated vacations, because I had little interaction with other people outside of school. 

Now, I am much more personable. Still quite scholarly.  I have, however, traveled the world. I have met and interacted with interesting and fun people everywhere I've been. If you want to find out, contact me.  I try to help everyone who does.  I also still play games just now Warhammer and Warhammer 40K :-).  

So gentle reader, the ides of August are upon us.  That means that goals slated for accomplishment this year had better be in sight! If you have a clinical candidate in your goals, you had better have your scale-up worked out and your animals ordered for those remaining pharmacology studies and dose ranging tox and PK. If you have programs finishing up, hopefully the screening campaigns are done, so you can order resupply on the hits and you can validate them before the end of the year and have a chance of getting the work done to start on the hit to lead for next year.  If those hit-to-lead campaigns are supposed to move into lead optimization you had better be seeing your primary assay start to produce results that promise the hope of seeing in vivo activity.  That and the annual ritual of filling out your budget like a kid filling out his Christmas list only to have Santa turn into the Grinch and arbitrarily cut 50% off the top.

Ah the Ides of August!

So I want to offer you some help.  If you are stuck optimizing your leads, Victrix can help with structure based and ligand based methods.  If new chemical matter is what you are looking for, we can pull bioisosteres out that will surprise you. Virtual screening, both structure and ligand based can help bring ideas into play that you haven't thought of.  We can help you mine your HTS data and determine false positives and flag potential false negatives for follow-up.  We can build custom PK and tox models to help you out of your DMPK problems.  

It's so cheap, you can't afford not to. Call us for an evaluation.  We will work with your chemists and biologists to give you access to a state of the art computational chemistry and molecular modeling department that uses the same tools as big pharma and the best computational departments with expertise that is the best in class.  I'm sure you are thinking that you can't afford it.  But you can.  You don't need it all the time.  You only pay for access to the tools and expertise you need, when you need it.  Save you head count for another medicinal chemist who can make compounds or another biologist who can generate precious, precious data.  Let us be your computational group.  The only thing you might miss is that sinking feeling when this year’s goals slip out of sight, and you weren't really looking forward to that anyway, were you?




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Fierce Biotech reports that only thirteen new entities were approved in the first half of the year, but cautions that it may not be as bad as it looks. If you have been reading my blog, you know I am a bit of a contrarian, and I disagree.  It looks bad. These are the drugs predicted to be blockbusters:

Full disclosure:  I work with Collaborative Drug Discovery.  I use and love their product.  You may, therefore, take this post with a grain of salt. Nonetheless, I advise you to give the system a solid look.  It is cost effective and easy to use.  If you and your users are familiar with recent generation web apps, you will have an intuitive understanding of the interface.  

Now with that out of the way, What the heck am I talking about? Here is an article on the CDD web site about what is in it for you.  Read it.  Then come back. 

Ok, that was pretty interesting, right?  You see even small startups and academics produce data.  My guess is that if you haven't given this any thought, you are using excel spreadsheets to manage your data.  This is an invitation to disaster.  Registering compounds, tracking their physical properties and biological assay data is something you should be able to do.  You should be able to control access to the data in a straightforward manner. You shouldn't have to pay to maintain an IT infrastructure you don't need.  CDD's cloud based solution addresses all these issues.  Do yourself a favor, and get it today!

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