Overview

                                                                                                   

The Drug Discovery and Informatics (D2I) group at Midlands State University, within the Chemical Sciences Department, is a research team in Zimbabwe that centers its efforts on chemogenomic-driven drug discovery for infectious diseases, particularly focusing on Malaria and Tuberculosis, and concurrently addressing the challenges linked to Cancer.

The research activities outlined encompass a diverse array of drug discovery strategies utilizing computational and experimental approaches. These endeavors are primarily focused on identifying and optimizing inhibitors for various biological targets and identifying targets for known bioactive compounds, with a common goal of developing novel therapeutic interventions. The methodologies employed include structure-based design, quantitative structure-activity relationship (QSAR) analysis, Artificial Intelligence/Machine Learning (AI/ML) modeling, synthesis and biophysical/biochemical assays. The research group also engages in collaborative research activities with several institutions, including H3D at the University of Cape Town, the University of Venda, the University of Zambia, and the University of Malawi.

The Drug Discovery & Informatics research group: Front row, from left Sithulisiwe Ngwenya (Researcher), Prof Upenyu Guyo (Co-Principal Investigator), Tsungai Faith Manyadza (Researcher), Back row from Left: Dr Dubekile Nyoni (Researcher), Prof Grace Mugumbate (Principal Investigator), Blessed Mazarura (Researcher).

Research Objectives

The group’s main objectives are to:

  1. Identify Inhibitors of PfHsp for Malaria Treatment

Utilize ligand-based and structure-based virtual screening methods, along with machine learning techniques, employing bioactive data sourced from ChEMBL, PDB databases, and internal databases. The aim is to identify potential inhibitors of Plasmodium falciparum heat shock proteins for the development of malaria treatment drugs. Employ in-silico approaches to predict Absorption, Distribution, Metabolism, and Excretion (ADME) properties, cytotoxicity, and hERG inhibition of selected compounds. This step involves assessing the pharmacokinetic and safety profiles of the identified compounds.

  1. Experimental Validation of PfHsp Inhibitors

Validate the in silico PfHsp-ligand pairs (hits/firstpoint) through a combination of anti-Plasmodium whole cell assays, biophysical techniques, and biochemical in vitro experiments. This step ensures the biological relevance and efficacy of the identified compounds in inhibiting PfHsp.

  1. Structure-Based Optimization of the hits and In vitro Assays

Conduct structure-based optimization of the hits by modifying the structures of highly active compounds, guided by the physicochemical properties of the PfHsp binding pocket and medicinal chemistry principles. Follow up with in vitro assays to determine the activities of the optimized compounds, ensuring their potential as effective inhibitors. To enhance the efficacy of hit compounds identified in our screenings, Quantitative Structure-Activity Relationship (QSAR) modelling will be employed. This approach will allow us to systematically analyse the relationship between the chemical structure of our compounds and their biological activities. Ultimately, this will aid in the identification of lead compounds with the potential for further development into effective therapeutics.

  1. Optimisation of Lead Compounds to give candidate compounds.

Systematically select active compounds based on the outcomes of in vitro assays, designating them as leads for subsequent modification. This step is crucial for advancing the drug development process and refining the identified compounds into candidates with enhanced therapeutic potential.

 Research focus

Malaria Research:

A significant portion of the research is dedicated to combating malaria, a life-threatening disease caused by Plasmodium falciparum. One approach involves the chemogenomic-guided identification and optimization of inhibitors targeting heat shock proteins. Additionally, structure-based design and synthesis of tetrahydro-1,3,5-triazin-2-amine derivatives are explored as potential anti-malarial drugs. In-silico methods are also employed to identify P. falciparum targets and screen for antimalarial phytochemicals from Cassia abbreviata Oliv. These multifaceted strategies highlight a comprehensive effort to discover and develop effective treatments for malaria.

Tuberculosis (TB) Research:

The research extends its scope to tuberculosis, with a focus on tetrahydro-1,3,5-triazin-2-amine derivatives as inhibitors of Mycobacterium tuberculosis dihydrofolate reductase. The investigation includes structure-based hit-to-lead optimization design, along with the assessment of pharmacokinetics, pharmacodynamics, and molecular dynamics simulations. This intricate approach aims at developing potent inhibitors to combat Mycobacterium tuberculosis, contributing to the ongoing efforts to address the global challenge of drug-resistant tuberculosis.

Cancer Research:

In the realm of cancer research, the emphasis shifts towards the discovery of potential Gamma secretase inhibitors for breast cancer therapy. Utilizing chemogenomic methods, this research seeks to identify and optimize compounds that could serve as effective inhibitors. The project reflects a targeted approach to cancer treatment, exploring avenues that leverage computational tools to guide the discovery and development of novel therapeutic agents for breast cancer.

List of Research Projects

  1. Chemogenomic-guided identification and optimization of inhibitors for Plasmodium falciparum heat shock proteins as potential antimalarial drugs.
  2. Potential Gamma secretase inhibitors identified from chemical space and QSAR analysis.
  3. Structure-based design and synthesis of tetrahydro-1,3,5-triazin- 2-amine derivatives for anti-malaria drugs.
  4. Structure-based hit-to-lead optimization design, ADMET, and Molecular Dynamics of tetrahydro-1,3,5-triazine-2-amine derivatives as inhibitors of Mycobacterium tuberculosis Dihydrofolate Reductase.
  5. In-silico identification of Plasmodium falciparum target, and antimalarial phytochemicals from Cassia abbreviata
  6. Structure-based identification of Plasmodium falciparum heat shock proteins 70-z inhibitors as potential anti-malarial compounds.
  7. The discovery and development of Plasmodium falciparum Heat shock protein 70-1 inhibitors using computer-guided approaches.
  8. Discovery of Gamma secretase inhibitors for breast cancer therapy through chemogenomic methods.
  9. Strengthening the fight against malaria: Artificial Intelligence Driven Optimisation and Synthesis of Quinoline Derivatives as Inhibitors of PfHsp70-1.

Research Output

The research group has generated two homology structures of PfHsp70-1 and PfHsp70-z, these have been successfully used in structure-based screening. Through the use of chemogenomic screening and biochemical assays, the team has identified fourteen confirmed antimalarial hits from the Medicine for Malaria Venture (MMV) library. The activity of these compounds in biological assays targeting Plasmodium falciparum Heat shock protein 70-1 (PfHsp70-1) ranged from 0.027µM to 7.67µM. A total of thirteen compounds have also been identified from the MMV library, these are targeting PfHsp70-z, additionally nine more compounds have also been identified from the H3D library. These are currently undergoing hit-validation in whole-cell biological assays. While focusing on the 1, 3, 5-triazine scaffold, the group has designed, optimized and synthesized six antimalarial and anti-tuberculosis compounds targeting PfHsp70-1 and Mycobacterium tuberculosis dihydrofolate reductase (MtbDHFR), these are also undergoing hit-validation in biological assays. Working on the discovery and development of antimalarial compounds from natural products driven by Machine-Learning, eight compounds were identified from Cassia abbreviata Oliv, these compounds are targeting Plasmodium falciparum Isolate K1. This approach is in line with the Zimbabwe’s Education 5.0 principles and the Drug Discovery and Informatics (D2I) group places equal emphasis on natural products and synthetic compounds as potential valuable sources for drug development. Another area our group is focusing on is the discovery of anti-breast cancer compounds through cheminformatics and AI/ML. The study identified and validated the DYIGS motif as the primary binding site on Nicastrin for potential breast cancer drug development. Insights into key interacting residues offer guidance for designing small molecules targeting Nicastrin inhibition.

Current Work

In an effort to optimize these compounds for better potency, the group has embarked on a new phase, driven by the optimization and synthesis of the structural analogs. Some of the synthesis materials and laboratory equipment has been purchased to aid the synthesis of sixteen compounds targeting Pfhsp70-1.

Future plans

As we look towards the future, the Drug Discovery and Informatics (D2I) group is committed to expanding our drug discovery and development efforts to address emerging infectious diseases and various forms of cancer. Our vision encompasses advancing drug discovery methodologies while developing novel tools and methods to streamline the process. To accelerate the translation of their research findings into practical applications, the group looks forward to actively collaborate with industry partners and other departments at Midlands State University (Pathology, Medicine, Biology and Biochemistry).