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Principal Investigator: Enrico Tapavicza
Organization: CALIFORNIA STATE UNIVERSITY LONG BEACH
Fiscal Year: 2023
Award: $147,500
Funding agency: National Institute of General Medical Sciences
Project Summary/Abstract
There is a dire need in developing new molecular paradigms for pharmacotherapy to address problems of poor
drug selectivity, causing side effects, drug resistance, and environmental toxicity. Currently, over 85 % of the drugs
in clinical research are discarded due to poor selectivity. Increasing drug selectivity is a major concern of modern
drug development. Photopharmacology increases drug selectivity by using controlled light-activation of drugs at
a given time and location in the body. Recently, a light-driven molecular nanomotor has been developed (García-
López et al., Nature, 548, 7669, 567, 2017), that is capable of disrupting biological membranes, inducing cell
death in eucaryotic cells. This mechanism has potential applications in drug delivery through lipid nanoparticles,
cancer treatment, and combating infectious diseases. Besides chemotherapy, radiation, and surgery, mechanical
action of nanomotors on a molecular level could become a fourth modality in the treatment of patients. However,
being still at a developmental stage, a detailed understanding of the molecular mechanism of this process is
required to advance this technology towards clinical applications. We will use computer modeling to study the
molecular mechanism of the membrane disruption by the recently developed nanomotor. Based on the gained
insight, we will design and optimize new nanomotors by introducing functional groups to improve molecular prop-
erties. The final goal is to develop a next generation of nanomotors that can be applied in clinical studies. To
reduce phototoxicity, it is necessary that the motor operates with a high quantum yield, converting a high percent-
age of the absorbed photons into mechanical work to displace membrane lipids. Furthermore, tissue applications
require the irradiation wavelength to occur in the 600–1000 nm region, which penetrates deeper than the initially
used ultraviolet light, that also has higher phototoxicity. We will employ computational methods based on quantum
mechanics, molecular mechanics, and machine learning. Core of our study will be the real time simulation of the
photoinduced dynamics of the nanomotor in the membrane, yielding atomistic information about the membrane
disruption process. To this end we will use machine learning driven molecular dynamics. The machine learning
algorithm will be trained using quantum mechanical simulations. Based on the gained insights, several molecular
properties will be enhanced by modifications of the functional groups: a) binding affinity to the membrane; b)
light absorption in the near infrared or visible region; c) absorption cross section and quantum yield. To obtain
candidate molecules we will employ in silico high-throughput screening based on exhaustive molecule generation
and machine learning of quantum mechanical properties. Candidates with improved properties will be synthe-
sized by the García-López lab and studied experimentally to gauge the validity of the predictions. The results
of this combined computational/experimental study will give a detailed atomistic picture of the dynamics of the
nanomotors membranes. The proposed molecular modifications will lead to a next generation of nanomotors,
opening this technology for clinical studies, leading to highly selective light-activated drugs.
Terms: <2-photon><Actinic Rays><Address><Adverse effects><Affinity><Antibiotic Therapy><Antibiotic Treatment><Bacterial Antibiotic Resistance><Binding><Biological><Body Tissues><Cancer Treatment><Cell Body><Cell Death Induction><Cell Membrane Lipids><Cell membrane><Cells><Clinical Research><Clinical Study><Collaborations><Communicable Diseases><Computer Models><Computer Simulation><Computer based Simulation><Computer software><Computerized Models><Computing Methodologies><Cytoplasmic Membrane><Development><Drug Controls><Drug Delivery><Drug Delivery Systems><Drug Therapy><Drug resistance><Drug usage><Drugs><Employment><Gases><Generations><Goals><High Throughput Assay><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Isomerism><Light><Location><Machine Learning><Macromolecular Structure><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Measures><Mechanics><Mediating><Medication><Membrane><Membrane Lipids><Methods><Modality><Modernization><Modification><Molecular><Molecular Dynamics Simulation><Molecular Interaction><Molecular Structure><Motor><Nature><Nuclear><Operative Procedures><Operative Surgical Procedures><Patients><Penetration><Perforation><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Phase><Phosphatides><Phospholipids><Photons><Photoradiation><Phototoxicity><Plasma Membrane><Process><Property><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Quantum Mechanics><Radiation><Radiation induced damage><Rotation><Software><Structure><Surgical><Surgical Interventions><Surgical Procedure><System><Techniques><Technology><Testing><Therapeutic><Time><Tissues><Toxic effect><Toxicities><Training><UV light><UV radiation><UV rays><Ultraviolet Rays><Work><absorption><anti-cancer therapy><antibiotic resistant bacteria><anticancer therapy><bacterial antibiotic resistant><bacterial disease treatment><bacterial infectious disease treatment><bacterial resistance to antibiotic><biologic><cancer cell><cancer therapy><cancer-directed therapy><chemotherapy><clinical applicability><clinical application><computational methodology><computational methods><computational modeling><computational models><computational simulation><computer based method><computer based models><computer methods><computerized modeling><computerized simulation><computing method><design><designing><developmental><double bond><drug development><drug resistant><drug treatment><drug use><drug/agent><experiment><experimental research><experimental study><experiments><functional group><high throughput screening><improved><in silico><insight><irradiation><isomer><light intensity><lipid based nanoparticle><lipid nanoparticle><machine based learning><machine learned algorithm><machine learning algorithm><machine learning based algorithm><mechanic><mechanical><mechanical properties><membrane structure><molecular dynamics><molecular mechanics><nano><new approaches><next generation><novel approaches><novel strategies><novel strategy><pi bond><plasmalemma><quantum><radiation damage><resistance to Drug><resistant to Drug><side effect><simulation><surgery><two-photon><ultra violet><ultra violet light><ultra violet radiation><ultra violet rays><ultraviolet><ultraviolet light><ultraviolet radiation>