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I'm Back

5/6/2018

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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!

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Reflections on World TB Day

3/24/2014

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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. 


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The Five Biggest Mistakes of Start-Up or Early Stage Biotech/Pharmaceutical Companies

3/3/2014

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Starting a drug discovery endeavor is daunting task.  Without question, no one can know everything about a subject as vast as drug discovery.  There are resources out there to help, but often, scientists don’t know about them.  They are usually experts in their fields, but not in the many areas that are necessary to successfully navigate the difficult landscape of biotech-pharma start-up.  These are the five biggest mistakes I have encountered in my career:

1.       Not taking care of ones data.  Often a start-up or early stage company will have a bare minimum of personnel. The most common thing I have seen is storing biological and chemical data in flat files like spreadsheets or SDfiles. This makes them impossible to search, difficult to make sure everyone in your organization has access to the most current data, and prone to corruption and loss.  Start-up scientist from an academic background often don’t know about integrated cheminformatic and high throughput screening data management systems.  Scientists from a big pharma background usually associate these systems with expensive, cumbersome commercial systems, or even more cumbersome and expensive custom built systems.

The truth is flexible, easy to use, and cost effective systems exist that can solve all one data management issues.  I recommend CDD Vault™ to my clients. It is a private hosted solution, using a familiar web interface, removing all of the overhead in setting up a database.  Do yourself a favor, and check it out.  You will simplify your life and eliminate the hassles of managing your data.

2.       Doing without, when you can’t afford a full time hire.  Time and time again, I’ve seen: Companies founded by biologists do without chemistry support, Companies founded by chemists outsource their biology, and Companies with both do without specialist input like computational chemistry, chem- or bioinformatics, DMPK-Tox, or preclinical research.  It is easy to hire experts and affordable costs and keep them on call by negotiating a contract that guarantees them a minimum revenue to have them there when you need them.  Victrix provides these types of arrangements all the time.  I know other consultants do as well.  If you need any of this kind of support, but can’t afford to a full time hire, we can help you find the expert you need with our extensive range of contacts.

3.       Not having your outsourcing professionally managed.  I’ve had significant experience in locating, negotiating and managing chemical and biological service outsourcing.  I also make significant use of virtual assistants.  If you need a project outsourced, or are interested in making use of virtual assistants to streamline your operations, schedule a free evaluation.  We are running a 50% off special during the month of March. Our $10K outsourcing management fee is now $5K, and when your project is finished, you will be professionally trained to take over yourself on managing your project.

4.       Bringing your big pharma baggage with you to a start-up.  I’ve seen small companies saddled with the bureaucracy of a multinational company by well-meaning scientists who try to recreate the system they left behind at a large pharmaceutical company in their new smaller digs.  All this does is make, what should be a productive, nimble small company as unproductive as a sclerotic giant.  It’s natural to try to create the familiar in new circumstances, but often in creating a familiar cocoon we bring all the problems of the past with us.  Remember you aren’t at a mega-company where 100’s of people need to sign off on new or changed projects, don’t complicate the simple. Do what needs to be done, even if it violates some rule you were taught at your previous big company.

5.       Not keeping your eyes on the prize.  Despite the fact that we would all like to have infinite time and resource to find the perfect drug, the issue is no one is interested in you until you have de-risked your compound through Phase II.  This is the sad truth, but everyone should be focused on this goal and be working toward it. 


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Influenza, Depression, Encephalitis lethargica and the Viral World we Live in. 

1/29/2014

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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!

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Victrix offers business development services.

10/5/2013

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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. 

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Have we gone over the top with analyses of marketed drugs and persecuting those who make compounds outside of the rule of the month?

9/4/2013

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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.  

As always follow Victrix on LinkedIn if you enjoy the blog!



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Portrait of the Scientist as a Young Nerd

9/2/2013

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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 :-).  

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It's the middle of August. Do you know where next years leads are?

8/14/2013

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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?




If you enjoy my blog, follow VictrixCMC on LinkedIn, Facebook, and Twitter (@VictrixCMC)

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The results are in and they are not good...

8/6/2013

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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:

  • Tecfidera (multiple sclerosis): $4.2 billion, Biogen-Idec, dimethyl-fumarate
  • Kadcyla (breast cancer): $2.9 billion, Genentech, antibody conjugate
  • Breo Ellipta (COPD): $1.84 billion, Glaxo+Theravance, Steroid+beta2 agonist
  • Pomalyst (multiple myeloma): $1.28 billion, Celgene, Thalidomide analogue
  • Nesina (diabetes): $1.1 billion, Takeda, DPP4 inhibitor
I'm concerned that there isn't a lot of innovation there.  Breo Elipta is great for Theravance, but it shows that Glaxo has to look elsewhere for innovation.  I've commented before on the inherent problems with DPP4 and the incretin pathway.  Pomalyst is yet another Thalidomide analogue.  This time, at least, it is approved for a solid tumor indication.  Kadcyla is a biologic, and not to denigrate biologics, I'm an orally bioavailable, small molecule guy. I don't get the fumaric acid dimethyl ester.  It's been used since the 50's, is a biocide, and I wonder how it's going to generate $4.2 billion.  

This trend concerns me.  Which brings me to you dear reader.  It's August.  Do your goals include any IND's or clinical candidate nominations for this year?  If so you better have a good scale up route in place to your shot on goal, because it's now officially too late to pull one out of the hat at the last minute.  Also Do you know where your lead series are for next year?  It's time to get cracking.  You need your new chemical mater in place for next year, like last week, dude! Victrix can help.  We are experts at data mining, virtual screening and hit to lead strategies.  Contact us and lets talk about your needs.  It's free.  We will even visit your site and give you an analysis of your needs for free.  Mention this blog for 2 free hours of consulting on top of our free discovery. I'm worried about you and I don't even know you. I want you to meet your goals this year and be in position to get a head start on next years' goals.  You have

If you enjoy my blog, follow VictrixCMC on LinkedIn, Facebook, and Twitter (@VictrixCMC)

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Manage your Data in a Secure System or Loose it.

8/2/2013

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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!

If you enjoy my blog, follow VictrixCMC on LinkedIn, Facebook, and Twitter (@VictrixCMC)

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    Our CSO sounds off about drug discovery, computational chemistry and history

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