Molecular visualization and analysis of structural features are essential elements in the understanding 3D structure of proteins, peptides, and nucleotides. The design of molecular complexes of the above biopolymers with small molecules or peptides (e.g., inhibitors) becomes significantly enabled with proper and helpful tools. Such tools and methods thus form an essential part of the structure-based drug design (SBDD).
Consulting Services in Drug Discovery
Bright Rock Path, LLC (BRP) provides consulting and advising services to entities ranging from start-up to large companies, CROs, academic groups, nonprofit patient, and government research agencies in support of their internal drug discovery programs.
BRP offers services in foremost areas of the drug discovery (early-stage to clinical). BRP also provides consultancy to fill temporary skillset gaps.
While residing in the USA, BRP reaches globally and across multiple time zones.
Areas of core expertise:
- Medicinal chemistry, Computational chemistry, Organic chemistry, Analytical chemistry, Peptide chemistry.
- Structure-activity relationship (SAR) and multi-parametric optimization of small organic molecules and peptides.
- Hit to lead process including compound optimization & establishing intellectual property (IP).
- Support in writing research grants in the area of drug discovery (e.g., R03, R21, R01, SBIR-SSTR).
- Structure-based design, cheminformatics, machine learning.
- Professional management of client's projects, external CROs, and collaborative projects involving academic teams.
Drug Discovery
Drug discovery is as a multistage process involving critical milestone objectives. In the early drug discovery segment, which is the area of our expertise, major milestones include: a) proposal addressing a new medical need and preferred therapeutic agent, b) formulating and validating the hypothesis of potential target or phenotypic readout with clinically relevant in vitro and in vivo validators, c) set of biochemical and cellular assays, d) hit identification, e) hit expansion, f) lead identification and optimization, g) pre-clinical toxicity and pharmacology assessment. With a strong background in Medicinal chemistry and related disciplines and with more than 20 years of experience in drug discovery, we are confident in guiding our clients through the early-stage drug discovery landscape.
Analytical Chemistry
For many years, HPLC-MS systems played a critical role in drug discovery. There are several configurations in which HPLC-MS instruments are used for high throughput quality control of compound libraries or compounds made during series optimization. With the integration of ADME protocols into the lead optimization phase, methods for HPLC or HPLC-MS assessment of compound kinetic solubility, logD, or chemical stability have been developed to support Medicinal chemistry campaigns. Contemporary Analytical Chemistry is a multidisciplinary field spanning from contaminant detection to an enzyme or cell-based assay to modern ion-trap multi-sector MS-MS separations and ion detection. BRP provides assistance with method development and implementation of techniques that support early-stage drug discovery process.
Computational Chemistry
Hardware and software advances in contemporary structure-based design tools together with the availability of the target 3-D structural data are not only at the heart of modern in silico drug discovery but also provide an invaluable stimulus for medicinal chemists. Understanding the interactions between biopolymers and their ligands is key to designing hypotheses formulated during the drug optimization process. A wide range of relevant physical quantities such as molecular dipole moments, polarizability, interaction energies, acido-basic properties, solubility, and partition coefficients are concepts that Medicinal chemists utilize in the design and optimization of lead series. BRP assists with implementation and use of basic open-source tools for daily work of Medicinal Chemists.
About the founder
Marcel has a wealth of expertise gained from his time as a drug discovery scientist and manager in biotechs and large pharmaceutical companies. Most recently, he led the Chemistry and Analytics groups in support of drug discovery programs at Sanofi and Icagen, Inc. Marcel has extensive experience in the early-stage drug discovery, multiple disease areas, target classes, and bioactive chemotypes. Over the years, he has been embracing multi-disciplinary approaches to the discovery of new medicines, particularly in stages of the hit to lead and lead to the clinical candidate. [Personal LinkedIn profile]
Marcel is the founder and principle at the Bright Rock Path, LCC. [Company LinkedIn profile]
Qualifications attained over 20 years of experience in a variety of drug discovery settings include:
- Extensive experience in small molecule and peptide drug discovery across multiple therapeutic areas from target identification through clinical evaluation.
- Experience in multiple target classes and target class chemotypes including ion channels, kinases, GPCRs, and nuclear hormone receptors.
- Biotech-born, pharma-sharpened expertise in Medicinal chemistry, drug disposition (ADME), structure-based drug design and in-silico methods, and Analytical chemistry.
- Practical understanding and expertise in integrating principal activities supporting drug discovery (building a screening collection, compound registration, sample storage, QC, physico-chemical properties, ADME, in vitro assays, hit/lead/candidate optimization).
- Project management across global research groups and diverse cultures.
... by a Topic
The following panels detail typical activities encountered during the early stages of drug discovery. BRP offers consultation and advise across multiple disciplines and topics.
Hits and Leads
- Series expansion and multi-parametric optimization
- Identifying SAR for primary activity, selectivity, and ADME properties
- Identifying tractable scaffold candidates for lead selection
- Re-scaffolding, synthesis, IP driven SAR
- ADME, PK, and acute toxicities of chemical class
- Structure re-optimization based on Metabolite ID results
Compound Libraries
- Library design, format selection, virtual collections
- Target family biased vs. diverse sets
- FDA-approved drugs, pharmacologically active compounds
- An established network for compound sourcing and custom synthesis
- Virtual screening collections
- Chemotype trackability, IP space
Methods and Processes
- Solid phase synthesis
- Peptide chemistry
- Combinatorial and high throughput chemistry
- Compound purification and archival
- Quality control and physico-chemical properties
- Integration of disciplines
Scripting and Programming
- Data analysis in Python
- Jupyter notebook/lab workflows
- RDKit, KNIME, PubChem, CHEMBL
- UCSF Chimera, PyMol
- Machine learning, Deep learning (DeepChem)
- Predictive models
Structure-based Design
- In silico QM prediction of stereoelectronic properties
- Binding site analysis
- Cheminformatics
- Compound design based on pharmacophore models
- Target-ligand docking and ligand conformational preferences
- Compound optimization based on in silico hypotheses
Analytical Chemistry
- Quality control and method development
- Analytical methods in early drug discovery
- Interpretation of chemical stability
- Process integration
- Data processing
Blogs and News
Recent publications:
Cai, S.; Moutal, A.; Yu, J.; Chew, L. A.; Isensee, J.; Chawla, R.; Gomez, K.; Luo, S.; Zhou, Y.; Chefdeville, A.; Madura, C.; Perez-Miller, S.; Bellampalli, S. S.; Dorame, A.; Scott, D. D.; François-Moutal, L.; Shan, Z.; Woodward, T.; Gokhale, V.; Hohmann, A. G.; Vanderah, T. W.; Patek, M.; Khanna, M.; Hucho, T.; Khanna, R. Selective Targeting of NaV1.7 via Inhibition of the CRMP2-Ubc9 Interaction Reduces Pain in Rodents. Science Translational Medicine 2021, 13 (619). Link
Perez-Miller, S.; Patek, M.; Moutal, A.; Duran de Haro, P.; Cabel, C. R.; Thorne, C. A.; Campos, S. K.; Khanna, R. Novel compounds targeting neuropilin receptor 1 with potential to interfere with SARS-CoV-2 virus entry. ACS Chem. Neurosci. 2021, 12 (8), 1299-1312. Link
Khanna, R.; Moutal, A.; Perez-Miller, S.; Chefdeville, A.; Boinon, L.; Patek, M. Druggability of CRMP2 for Neurodegenerative Diseases. ACS Chem. Neurosci. 2020. Link
Cai, S.; Tuohy, P.; Ma, C.; Kitamura, N.; Gomez, K.; Zhou, Y.; Ran, D.; Bellampalli, S. S.; Yu, J.; Luo, S.; Dorame, A.; Ngan Pham, N. Y.; Molnar, G.; Streicher, J. M.; Patek, M.; Perez-Miller, S.; Moutal, A.; Wang, J.; Khanna, R. A Modulator of the Low-Voltage Activated T-Type Calcium Channel That Reverses HIV Glycoprotein 120-, Paclitaxel-, and Spinal Nerve Ligation-Induced Peripheral Neuropathies. Pain 2020. Link
Zhou, Y.; Cai, S.; Moutal, A.; Yu, J.; Gómez, K.; Madura, C. L.; Shan, Z.; Pham, N. Y. N.; Serafini, M. J.; Dorame, A.; Scott, D. D.; François-Moutal, L.; Perez-Miller, S.; Patek, M.; Khanna, M.; Khanna, R. The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels. ACS Chem. Neurosci. 2019, 10 (12), 4834–4846. Link
Blog
23Jul
Video
An engaging video story showcasing scientific insights, company overview and our connection with UAVenture Capital. For more information on the company visit www.regulonix.com.
Download BRP slides
- About the company
- Value proposition and client organizations
- Supported activities in drug discovery by topics with details
- Computational chemistry and structure-based design
- Chemoinformatics, machine learning, Jupyter notebooks
- Small molecules and peptides solution- and solid-phase chemistry
- Design of screening collections
BRP Clients
Regulonix
"Non-opioid drugs for chronic pain to attack a global health epidemic." The approach pursued by Regulonix primarily modulates trafficking of the Nav1.7 sodium channel through a protein called CRMP2, or collapsing response mediator protein 2. Scientists and founders of Regulonix have invented and are developing a new class of non-opioid compounds to treat pain.
ProteinQure
Designing computational R&D tools to perform in silico drug design. The group at ProteinQure is leveraging quantum computing, quantum alghorithms, molecular simulations, and reinforcement learning to engineer novel therapeutic solutions.
University of Arizona
Support of academic research groups with a focus on the design of new therapeutics and understanding of the effects of compounds on disease state.
- - Providing expert insights into drug discovery.
- - Advice and input into experimental design.
- - Input into grant applications and scientific papers.
Center for Innovation in Brain Science (CIBS)
The CIBS environment integrates collaborative research through innovative team science. The team has expertise spanning discovery, translational, regulatory, and clinical science. BRP supports CIBS investigators in developing new therapies for Alzheimer’s, Parkinson’s, Multiple Sclerosis, ALS (Amyotrophic Lateral Sclerosis), aging, and other complex neurodegenerative diseases.
The May Khanna Laboratory
The lab is developing small molecule therapeutics for neurodegenerative diseases. This phenomenal group of scientists combines biochemical and biophysical techniques to target key protein-protein and protein-RNA interactions to develop medicines for devastating diseases, such as Alzheimer's disease (AD) or Amyotrophic lateral sclerosis (ALS).
AIchemy
AIchemy focuses on building best-in-class machine learning models for creating protein kinase drugs. AIchemy built 3D models of every kinase in the kinome, in multiple active and inactive conformational states. Along with the state-of-the-art ML system, AIchemy is poised to find chemical matter for structurally novel and selective drugs.
Assorted Topics
Clearance in Drug Design.
An easy to read refresher on the key concept in Medicinal Chemistry - drug clearance. Simple formulas, helpful graphics, and main points for Medicinal Chemists: (1) Do not optimize molecule on binding. Rather optimize on unbound intrinsic clearance. (2) Pay attention to enzyme-transporter interplay and optimize compound series based on rate-determining mechanisms. (3) Maintain unbound concentrations below the Km of the enzymes/transporters clearing the series of molecules. Keep the dose/concentration relatively low.
eADME properties with differential mobility spectrometry and machine learning?
Perhaps an emerging method for fast characterization of compound series in drug discovery? Authors present the use of supervised machine learning to treat differential mobility spectrometry-mass spectrometry (DM-MS) data for ten topological classes of drug candidates. They demonstrate that the gas-phase clustering behavior can be used to predict the candidates\' condensed phase molecular properties, such as cell permeability, solubility, polar surface area, and water/octanol distribution coefficient. All of these measurements are performed in minutes and require mere nanograms of each drug examined.
Tuning Stacking Interactions between Asp-Arg Salt Bridges and Heterocyclic Drug Fragments.
Stacking interactions involving Asp-Arg and Glu-Arg salt bridges have been observed in protein-ligand complexes, yet not fully exploited in ligand design. Authors present accurate interaction energies for stacked dimers of a model salt bridge with 63 heterocycles commonly found in pharmaceuticals in both the gas phase and in a polarizable continuum model of ether. The strength of these interactions can be tuned over a 10 kcal/mol range in the gas phase and 5 kcal/mol in diethylether, highlighting an underappreciated means of tailoring ion-pair-pi interactions.
Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Cyclin-dependent kinase 2 (CDK2) activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors. This review discusses the latest understanding of the role of CDK2 in normal and cancer cells, outlines the core pharmacophores used to target CDK2, and summarizes strategies for the design of CDK2 inhibitors. However, despite many successful preclinical studies, results suggest that combination therapies may possibly be more effective than monotherapy.
Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis.
A comprehensive summary of current perspectives on the folding and misfolding of integral membrane proteins (MPs). The detailed account of the topic leads to a notion of clinical use of "pharmacological chaperones", a new class of small molecule that bind to and stabilize misfolded MP variants. Authors further outline linkages between MP misfolding and several human diseases, such as CMTA1, CF, Long QT Syndrome Cardiac Arrhythmia (KCNQ1), and Cardiac Arrhythmias (hERG, SCN5A). Next, authors summarize emerging chemical biology and medicinal chemistry approaches that directly address defects in MP folding.
Structure- and Ligand-Based Discovery of Chromane Arylsulfonamide Nav1.7 Inhibitors for the Treatment of Chronic Pain.
In this excellent paper, authors describe a novel series of arylsulfonamide inhibitors. A survey of the related literature revealed that previously discovered chemical matter suffered from poor physiochemical properties. An X-ray co-crystal structure of the inhibitor bound to VSD4 domain allowed pursuing structure-based drug design of arylsulfonamides further. Iterative optimizations led to the discovery of 24 which possesses excellent potency, metabolic stability, and good selectivity over other Nav isoforms. Compound 24 shows robust activity in a Nav1.7-dependent PK/PD model with an EC50 of 740 nM.
Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
The applications of fluorine in the design of drugs and agricultural chemicals continue to grow as our knowledge and understanding of how to take full advantage of the unique properties of this element matures. In this Perspective, the author provides a synopsis of some of the practical applications of fluorine as a bioisostere in drug design. I enjoyed reading this review a lot and consider it one of the most erudite articles on the subject.
UCSF Chimera for analysis of protein/ligand complexes and display of molecular surfaces.
A blog article featuring a general overview, installation, feature highlights, and several visual examples of UCSF Chimera.