M-Life’s™ Molecular Systems Approach Enables Understanding of Efficacy and Toxicity Origins at the Atomic Level Leading to the Next Generation for Drug Discovery

NASHVILLE, TENNESSEE – M-LIFE™ announced the successful conclusion of IL-6 molecular systems milestone pursuant to the advancement of a new generation of drugs. The milestone represents M-Life’s ability to decouple efficacy and toxicity and paves the way for new classes of Interleukin six (IL-6) inhibitors which aligns with the Company’s pursuit of offering better drugs for the treatment of chronic, quality of life conditions like Rheumatoid Arthritis (RA), Lupus, Crohn’s Disease and others. 
The four structures below are examples of M-Life’s™ IL-6 Molecular Systems work:

M-Life Image 1

Figure 1: M-Life™ modified curcuminoid compounds.
Dr. Peter Crooks, M-Life™ Chief Discovery Officer, said, “The structures shown illustrate key aspects of M-Life’s Molecular Systems work:  All four structures have the same basic scaffold;  however, both efficacy and the toxicities noted in Table 1 vary substantially across the four structures.  Toxicity tracks undesirably with increased efficacy.  Naturally, these curcumin-based analogs demonstrate the classic drug discovery challenge of designing molecules with high efficacy and low toxicity.”

M-Life Table 1

Table 1: Efficacy and toxicity data for the modified curcuminoid compounds.
Note:  The molecule description appears in column one. Column two shows the algorithm predicted efficacy as a fraction inhibition; columns 3 to 8 show predictions for common drug induced toxicities. 
 Crooks further explained, “In addition to curcuminoids, M-Life™ evaluated additional compounds as IL-6 inhibitors (a sample of those evaluated shown below).  Our algorithms ‘flagged’ argatroban, oxethanzaine, quinidine and sulphamethizole as being IL-6 active (shown in Table 2). While many of the compounds seemingly showed promise, a similar theme to the curcuminoids emerged when deriving analogs—efficacy and toxicity were coupled to varying degrees.”

M-Life Table 2

Table 2: On-Market Drugs and Botanticals Evaluated as Repurposed IL-6 Inhibitors.
Note: The toxicity predictive values are expressed as probabilities for which zero to 0.4 indicates a low probability of toxicity, >0.4 to 0.7 indicates moderate toxicity and 0.7 to 1.00 indicates a high degree of toxicity as supported by benchmarks.  These benchmarks include:  Losartan (QT score 0.39), Fenfluramine (QT score 0.57), Grepafloxacin (QT score 0.81), Clozapine (Agran - 0.70, MitoTox score – 0.75, and HepatoTox score – 0.90), Bromfenac (MitoTox score – 0.76, and HepatoTox score – 0.80), Suramin (Agran – 0.88, MitoTox – 0.66, Mutagenicity Score – 0.87, and HepatoTox – 0.94), Sanguarine (a phytochemical with a Mutagenicity score - 0.87), and Ketoconazole (HepatoTox Score – 0.84).  All benchmarks align with reported human toxicity data.

Dr. Jon Wilkes, M-Life™ Chief Scientist, described the Algorithm Team’s solution. “Dr. Crooks referred to the classical drug discovery conundrum,” he said, “however, M-Life’s™ Molecular Systems approach enabled us to understand the origins of efficacy and toxicity at the atomic level.  Algorithmically our proprietary P2L™ and MiST™ platforms accomplished identification and visualization of molecular interactions. And once we knew the individual atomic interactions that were involved, we accomplished conventional scaffold and substituent group alterations in a directed fashion.  Without knowledge of the molecular systems involved, we would have been operating essentially in the blind and never would have thought to make the alterations we madethe molecular systems knowledge was the key.” 

Presently, we have molecules with IL-6 efficacy scores in the 0.85 range with low toxicity across the board.  As an example, our IL-6 molecule MLS-IL-6P_0011 has a predicted IL-6 inhibition score of 0.83 with toxicity scores ranging 0.50 or lower.  While a 0.50 toxicity score may seem high, the over-the-counter drug Zantac and phytocompounds lutein and cannabidiol all have scores of 0.50-0.55 for QT/Torsade’s.  Overall, the M-Life™ IL-6 molecules showed more than 20 percent better predicted efficacy compared to the IL-6 inhibitors shown in Tables 1 and 2 – along with substantially lower toxicity across the board.”

M-Life™ IL-6 Program Summary
M-Life’s President and CEO Ted Moskal said, “Obviously we’re delighted with the progress of our IL-6 inhibitor program.  But more, this program illustrates the unique capabilities of our platforms which describe atomic features within a molecular systems environment.  This capability allowed us to make atom-by-atom changes to our molecules in a virtual environment and know the effects without there being existing examples of them.  By algorithmically describing atomic properties such as electro-negativity, nuclear composition and orbitals, we’re able to side-step the applicability domain issue that limits Artificial Intelligence/Machine Learning approaches.  And we believe our approach represents the next generation for drug discovery.”
About M-Life™ 
 M-Life™ is a life sciences, molecule discovery company focusing on the development of new drugs, agricultural and diagnostics related chemicals.   Whether a new antibiotic, non-opiate analgesic or environmentally friendly herbicide, the Company aims to address gaps in the present life sciences markets making life better.  To learn more about M-Life™, please visit us at www.m-lifesciences.com.
Contact Information:
Ted Moskal

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