Evolution of Drug Development and Regulatory Affairs: The Demonstrated Power of Artificial Intelligence.

PURPOSE: Artificial intelligence (AI) refers to technology capable of mimicking human cognitive functions and has important applications across all sectors and industries, including drug development. This has considerable implications for the regulation of drug development processes, as it is expected to transform both the way drugs are brought to market and the systems through which this process is controlled. There is currently insufficient evidence in published literature of the real-world applications of AI. Therefore, this narrative review investigated, collated, and elucidated the applications of AI in drug development and its regulatory processes. METHODS: A narrative review was conducted to ascertain the role of AI in streamlining drug development and regulatory processes. FINDINGS: The findings of this review revealed that machine learning or deep learning, natural language processing, and robotic process automation were favored applications of AI. Each of them had considerable implications on the operations they were intended to support. Overall, the AI tools facilitated access and provided manageability of information for decision-making across the drug development lifecycle. However, the findings also indicate that additional work is required by regulatory authorities to set out appropriate guidance on applications of the technology, which has critical implications for safety, regulatory process workflow and product development costs. IMPLICATIONS: AI has adequately proven its utility in drug development, prompting further investigations into the translational value of its utility based on cost and time saved for the delivery of essential drugs.

The Malaria Burden: A South African Perspective.

Malaria is a deadly disease caused by protozoan pathogens of the Plasmodium parasite. Transmission to humans occurs through the bite of an infected female Anopheles mosquito. According to the World Health Organization (WHO), an estimated 247 million cases of malaria were recorded worldwide in 2021, with approximately 619 000 malaria deaths. The initial signs of malaria can be mild and challenging to diagnose due to the signs and symptoms being similar to those of other illnesses. The malaria burden remains largely concentrated in the WHO sub-Saharan African region and has been recognised as a significant contributor to morbidity and mortality. This review aims to contribute to the existing knowledge on malaria in South Africa, a region within sub-Saharan Africa, focusing on the epidemiology and life cycle of the malaria parasite as well as diagnostic approaches for detecting malaria. In addition, nonpharmacological and pharmacological interventions for treating and preventing malaria infections will also be discussed herein. While there has been a significant reduction in the global burden of this disease, malaria remains a public health issue in South Africa. As such, the implementation of effective preventative measures and strategies, early diagnosis, and appropriate treatment regimens are crucial to reducing the malaria burden in South Africa.

VP40 of the Ebola Virus as a Target for EboV Therapy: Comprehensive Conformational and Inhibitor Binding Landscape from Accelerated Molecular Dynamics.

The first account of the dynamic features of the loop region of VP40 of the Ebola virus was studied using accelerated molecular dynamics simulations and reported herein. Among the proteins of the Ebola virus, the matrix protein (VP40) plays a significant role in the virus lifecycle thereby making it a promising therapeutic target. Of interest is the newly elucidated N-terminal domain loop region of VP40 comprising residues K127, T129, and N130 which when mutated to alanine have demonstrated an unrecognized role for N-terminal domain-plasma membrane interaction for efficient VP40-plasma membrane localization, oligomerization, matrix assembly, and egress. The molecular understanding of the conformational features of VP40 in complex with a known inhibitor still remains elusive. Using accelerated molecular dynamics approaches, we conducted a comparative study on VP40 apo and bound systems to understand the conformational features of VP40 at the molecular level and to determine the effect of inhibitor binding with the aid of a number of post-dynamic analytical tools. Significant features were seen in the presence of an inhibitor as per molecular mechanics/generalized born surface area binding free energy calculations. Results revealed that inhibitor binding to VP40 reduces the flexibility and mobility of the protein as supported by root mean square fluctuation and root mean square deviation calculations. The study revealed a characteristic "twisting" motion and coiling of the loop region of VP40 accompanied by conformational changes in the dimer interface upon inhibitor binding. We believe that results presented in this study will ultimately provide useful insight into the binding landscape of VP40 which could assist researchers in the discovery of potent Ebola virus inhibitors for anti-Ebola therapies.

Non-active site mutations disturb the loop dynamics, dimerization, viral budding and egress of VP40 of the Ebola virus.

The first account of the dynamic features of the loop region of VP40 of the Ebola virus (EboV) using accelerated molecular dynamics (aMD) simulations is reported herein. Due to its major role in the Ebola life cycle, VP40 is considered a promising therapeutic target. The available experimental data on the N-terminal domain (NTD) loop indicates that mutations K127A, T129A and N130A demonstrate an unrecognized role for NTD-plasma membrane (PM) interaction for efficient VP40-PM localization, oligomerization, matrix assembly and egress. Despite experimental results, the molecular description of VP40 and the information it can provide still remain vague. Therefore, to gain further molecular insight into the effect of mutations on the loop region of VP40 and its effects on the overall protein conformation and VP40 dimerization, aMD simulations and post-dynamic analyses were employed for wildtype (WT) and mutant systems. The results showed significant variations in the presence of mutations as per RMSF, RMSD, Rg, PCA and distance calculations in comparison to the WT. These results could provide researchers with insight with regards to the conformational aspects concerning VP40 and its close relation to the experimental data. We believe that the results presented in this study will ultimately provide a useful understanding of the structural landscape of the loop region of VP40, which would contribute towards the discovery of novel EboV inhibitors.

Ebola virus: A gap in drug design and discovery - experimental and computational perspective.

The Ebola virus, formally known as the Ebola hemorrhagic fever, is an acute viral syndrome causing sporadic outbreaks that have ravaged West Africa. Due to its extreme virulence and highly transmissible nature, Ebola has been classified as a category A bioweapon organism. Only recently have vaccine or drug regimens for the Ebola virus been developed, including Zmapp and peptides. In addition, existing drugs which have been repurposed toward anti-Ebola virus activity have been re-examined and are seen to be promising candidates toward combating Ebola. Drug development involving computational tools has been widely employed toward target-based drug design. Screening large libraries have greatly stimulated research toward effective anti-Ebola virus drug regimens. Current emphasis has been placed on the investigation of host proteins and druggable viral targets. There is a huge gap in the literature regarding guidelines in the discovery of Ebola virus inhibitors, which may be due to the lack of information on the Ebola drug targets, binding sites, and mechanism of action of the virus. This review focuses on Ebola virus inhibitors, drugs which could be repurposed to combat the Ebola virus, computational methods which study drug-target interactions as well as providing further insight into the mode of action of the Ebola virus.